British punk con artist Sarah Manning (Tatiana Maslany) sees an identical woman, Beth Childs, commit suicide by jumping in front of a train. Sarah retrieves Beth's bag, and finding that she is rich, decides to take her place, and clean out her bank account so she can collect her daughter Kira (Skyler Wexler) from her foster mother, Siobhan Sadler, whom Sarah calls Mrs. S (Maria Doyle Kennedy). Sarah asks her foster brother Felix Dawkins (Jordan Gavaris) to identify Beth's body as Sarah's to buy time for her scheme, and throw her drug-dealer boyfriend Victor Schmidt (Michael Mando) off her trail. Sarah withdraws $75,000 from Beth's account, but discovers to her dismay that Beth is a police detective suspended for shooting Maggie Chen. Beth's partner Arthur Bell (Kevin Hanchard) follows 'Beth,' and breaks into her car. Sarah is approached by Katja Obinger, another lookalike from Germany. Katja is killed by a sniper, but Sarah manages to escape.

Sarah is contacted by a woman who instructs her to dispose of Katja's body, and retrieve her briefcase. Art tells Sarah that he has the $75,000, and won't return it until she testifies at the inquest into Maggie Chen's shooting, and clears her name. It seems that Art placed a cellphone in the hand of the dead Maggie Chen to make it look like Beth had shot Maggie in self-defence, and he doesn't want this to get out. Sarah poses as Katja to get her briefcase from the hotel. Inside the briefcase, she finds evidence of more lookalikes, one of whom is Alison Hendrix, a soccer mom. Sarah gets Alison to set up a meeting where she meets yet another lookalike, evolutionary developmental biology student Cosima Niehaus, the woman she spoke with on the phone.

Alison tells Sarah that they are clones. In the briefcase, Sarah and Felix find that three of the clones Katja had found were already dead. Sarah goes to the police station to ask Art for the money back, only to be reinstated as a police detective, and drafted to cover Katja's murder. Worried that her fingerprints might be identical to Katja's she deletes them from the record. Art and Sarah track down the killer who starts shooting at them. Sarah saves Art's life, and then gives chase, only to find that the killer is another clone, Ukrainian Helena. Sarah stabs Helena, but Helena escapes. Art returns the money to Sarah, who gives it back to Alison, who had provided it to Beth to help with her investigation into their situation.

Sarah and Art continue looking for the killer, while Sarah tries to cover up that both killer and victim are her sister clones. The police believe that the killer is a fundamentalist Christian, while Cosima deduces that the group affiliated with Helena believe the clones are abominations and must be killed. Helena keeps a close eye on Sarah and the case, putting Sarah's cover in jeopardy. Mrs. S allows her to visit Kira, but because Sarah is busy working the case, Felix asks Alison to impersonate Sarah otherwise Mrs. S would never allow her to see Kira again. However, Alison is shocked to find that Kira knows she is not Sarah. Helena lures Sarah to Maggie Chen's apartment, where it is revealed that Maggie worked for the same group Helena works for; Beth actually killed Maggie to protect the clones. Sarah allows Helena to escape before Art arrives, and Sarah quits the police force. Helena collapses and gets picked up by a man wearing the same symbol as Helena and Maggie.

After waking up from a supposed dream where she was experimented on, Sarah spits out an electrode from her mouth. The clones soon learn that they have monitors, people in their lives whose purpose it is to observe them. Sarah suspects Beth's boyfriend Paul Dierden (Dylan Bruce) of being her monitor, while Alison suspects her husband Donnie (Kristian Bruun). Meanwhile, Vic comes across a chance meeting with Alison, and discovers that Sarah faked her death. In response, Sarah pays Vic $20,000 to leave her alone. Sarah and Felix spy on Paul's work place, but unknown to them, Paul follows Sarah walking Kira home from school. Paul also discovers that "Beth's" scar is gone. After calling Sarah to meet him at their home, Paul holds Sarah at gunpoint and demands an explanation, prompting Sarah to tell him that Beth is dead. When Sarah asks Paul why he is monitoring her, Paul admits that he does not know.

Alison purchases a nanny cam and finds that Donnie snuck out during the middle of the night. Paranoid, Alison ties him up, while also handling a house party featuring her neighborhood. Sarah impersonates Alison to question Donnie, who says he was covering up an extramarital affair. Paul follows Sarah and ultimately learns of their nature as clones. He also helps Sarah get rid of Vic when he continues to be a nuisance to her. Felix suspects Alison's neighbor, Aynsley Norris (Natalie Lisinska), of being the actual monitor. Meanwhile, Cosima is approached by Delphine Cormier (Evelyne Brochu), a fellow student. Cosima suspects Delphine of being her monitor, but goes with her to a lecture given by Dr. Aldous Leekie (Matt Frewer) of the Dyad Institute, a proponent of "neolution" (using technology to advance human evolution). Later, it is revealed that Delphine and Leekie are lovers.

Paul is questioned by his handler, Olivier Duval (David Richmond-Peck) regarding Beth's behavior. Though Paul tries to cover up the fact that Sarah is posing as Beth, the neolutionists discover the truth after checking the test results from experimenting on her. The neolutionists also believe Sarah to be the killer of the other clones. Meanwhile, Helena is nursed back to health by her trainer Tomas (Daniel Kash), who orders her to kill Sarah. Although she appears reluctant to do so, she implores Sarah to reveal the names of other clones. Later, Sarah calls Helena to help free Paul who is imprisoned in Olivier's nightclub, called "Neolution." Paul and Sarah hide out in Felix's loft to avoid the neolutionists. The police continue to investigate Katja's body and are perplexed to find a DNA match between the body and the killer, and that Katja's fingerprints also match Beth's.

Paul blackmails Olivier into telling Leekie that there was only one clone who attacked, Helena. Leekie tells Paul he has a new job for him, and then arranges for Olivier to be killed. Delphine tells Leekie that Cosima made a pass at her, and he pushes Delphine to find out how many clones Cosima has had contact with. Cosima and Delphine sleep together, and then Delphine spies on her, giving the names of the clones to Leekie, but neglecting to mention Kira. Art goes to the morgue to check 'Sarah's' body, and this leads him to Felix. They question Felix, and realize that he is the one who made an anonymous call to Art with information about Beth. Alison takes vengeance on Aynsley whom she suspects of being her monitor by having sex with her husband Chad (Eric Johnson). Aynsley finds out, and confronts Alison, and the two fight. Sarah introduces Alison to Mrs. S and tells her about the clones. While they are talking, Kira finds Helena at the front door, and follows her out into the street. Kira is very kind to Helena, but when she hears her mother call, Kira goes to find her, and gets hit by a car.

Kira is taken to the hospital, where it appears that she has accelerated healing. Alison returns home to find that Aynsley is holding an intervention regarding her past behavior and addictions, where under Felix's encouragement, Alison turns the tables by scrutinizing Aynsley. Art finds CCTV footage of the train station where Beth committed suicide, and discovers that Sarah has been impersonating her. Cosima learns that Delphine leaked the names of the clones to Leekie, and confronts her. Delphine reveals that she knows about Kira's existence but decided not to tell Leekie, knowing her life could come in danger should he know (Kira is the only known biological child of a clone). Sarah meets with Leekie, who wants her to save Helena from the Proletheans, the extremists who indoctrinated her. Tomas punished Helena for defying orders, but she is later rescued by Sarah, and turns against Tomas. They later return to Mrs. S, who has reached her contacts in England, and meet with Amelia (Melanie Nicholls-King), Sarah's birth mother. Amelia reveals that she give her away and fled after realizing she was a surrogate mother to Dyad scientists. Furthermore, Amelia gave birth to twins; Helena is Sarah's twin sister.

As Amelia meets Helena, police arrive to arrest Sarah, while Helena escapes. Sarah is about to tell Art the whole story, but gets spirited away by Daniel Rosen (Matthew Bennett), a Dyad operative. Sarah is brought to Rachel Duncan, a clone who is high in the Dyad organization. She offers Sarah and Kira protection. Leekie also offers the same to Alison and Cosima, as Cosima begins to display symptoms of a respiratory illness that Katja had. Alison confronts Aynsley a final time, ending with Alison watching Aynsley accidentally choke to death on her own scarf. Amelia tells a woman who appears to be Sarah that Mrs. S. is not who she says she is, but this 'Sarah' turns out to be Helena who stabs Amelia, blaming her for turning her over to the Proletheans. When Sarah finds her body, she shoots Helena. Alison signs Leekie's document, while Sarah goes to meet Rachel, planning to sign as well. However on the way, Cosima and Delphine decipher a code inside the clone genome; "this organism and derivative genetic material is restricted intellectual property". Cosima warns Sarah, who leaves Dyad before signing. She returns home to discover Mrs. S.'s home ransacked, and Kira and Mrs. S gone.

Sarah, believing that Rachel has Kira, asks Alison to get a gun for her, so she can get into Dyad. Sarah impersonates Cosima at a Dyad show, steals Leekie's passkey, and makes it to Rachel, only to find that Kira is not there. Alison is chosen as the lead in the community musical replacing the now deceased Aynsley.

Sarah tracks Kira to a hotel room, where Sarah is abducted only to find that Mrs. S. made it look like Kira had been kidnapped in order to get away. Kira no longer trusts Mrs. S., and when Sarah and Kira make a break for it, they find that Mrs. S.'s old friends planned to sell Kira to the Proletheans. Art is in danger of being suspended after a run-in with Daniel. Angela learns that Helena is in the hospital, but Helena is abducted by ranch Proletheans before she can see her. Cosima and Delphine set up a new lab at the Dyad Institute. Alison and Felix set a trap for Donnie, proving that he is Alison's monitor after all. The ranch Proletheans kill Tomas, and reveal plans to impregnate Helena to see if she can have a baby.

Sarah and Kira seek asylum at the home of Cal Morrison, one of Sarah's past lovers. Felix returns to the city to support Alison in her play, as her mental health suffers a downward spiral. Cosima and Delphine investigate the death of Jennifer Fitzsimmons, a clone who suffered from the same respiratory illness as Katja and Cosima. Daniel furthers his search for Sarah and Kira, while Art delves deeper into the mystery surrounding the Proletheans.

Sarah, Cosima, and Felix dig further into Mrs. S's past, leading them unexpectedly to Rachel's origins. Alison admits herself into rehab for her alcoholism but is forced to stay when Donnie intervenes. Helena escapes from the clutches of the Proletheans while Art scouts the perimeter of the compound. Cal protects Kira from harm as Sarah attempts to further uncover the mysteries in Rachel's past. Mrs. S rekindles an old flame.

Rachel wages war against Sarah, threatening the lives of everyone close to her. Sarah and Art continue to search for answers regarding Rachel's past while Helena goes on the offensive against Rachel. Cal continues his guardianship over Kira, and the Proletheans resort to extreme measures in order to further their goals. Leekie agrees to administer a new treatment for Cosima's illness against Rachel's orders as Paul succumbs to Rachel's influence.

Sarah and Helena embark on a road trip to Cold River to find Ethan Duncan. Helena's journey is interrupted by the appearance of Mark and Gracie, who try to convince her to return to the Prolethean compound. Art and Felix review the contents of Maggie Chen's locker to help Sarah in her quest. Sarah finds the home of Ethan Duncan, confronts an unexpected visitor, and learns important secrets about the clones' origins. Scott joins Cosima and Delphine at the Dyad Institute, discovering key genetic anomalies; while Alison encounters a familiar face at rehab.

Cal is forced to move Kira to a new location after his cover is compromised. Sarah leaves Ethan Duncan in the hands of Mrs. S in order to reconnect with Kira. While Alison and Vic prepare for Family Day at the rehabilitation center, Alison discovers Vic's plan to reveal her darkest secrets to Deangelis. Cosima begins the treatment for her respiratory illness while Delphine comforts her. Rachel reconnects with her father, as Leekie consults with Rachel's superior, Marion Bowles, about Sarah Manning. Alison reconnects with her children and confronts Donnie about his role as her monitor. Cosima discovers the truth about the origin of the stem cells used for her treatment, and Sarah regains guardianship over Kira. Donnie confronts Dr. Leekie.

Art receives a call on Beth's old cell phone from Tony, a transgender clone who promises his dying friend, Sammy, that he will deliver a message to Beth. Sarah and Mrs. S agree to transport Ethan Duncan to the Dyad Institute, hoping that his synthetic therapy will cure Cosima of her illness. Before he leaves, Ethan gives Kira a children's book that houses all of his secrets in its margins. Rachel takes control of the Dyad after Leekie's demise, and Cosima reveals 324B21's true identity to Scott. Felix houses Tony at his apartment and calls Sarah for help. Sarah arrives and reveals the truth behind Tony's origins, and Tony reveals Sammy's message, which implies that Paul may have a secret agenda. Alison helps Donnie cope with his killing of Dr. Leekie, and the two take measures to cover up the event. Cosima collapses and convulses in the presence of Delphine, Ethan, and Scott.

Kira undergoes bone marrow extraction in the hopes of halting the progression of Cosima's sickness. Ethan, Scott, and Cosima work to unlock the genetic sequences that caused the clones' respiratory illness. Rachel promotes Delphine to the position of Dyad director and begins to unravel emotionally, causing her to resort to drastic measures in order to further her goals. Alison and Donnie confront Vic and Deangelis while attempting to dispose of Leekie's body. Helena seeks vengeance against the Proletheans and helps Gracie and Mark escape from Hank's oppressive clutches.

Sarah surrenders herself to Dyad in an attempt to secure Kira's safety. Rachel transfers Delphine to Frankfurt so that she is no longer able to associate with the clones. Ethan makes the ultimate sacrifice in order to ensure that Project Leda does not continue. Kira steals a cell phone from a nurse and calls Cal who later appears at Mrs. S's door with key information that he learned after hacking into the computer of a Dyad double agent. Cal and Mrs. S make contact with the informant and ask for help releasing Sarah. Cosima, Scott, and Kira devise a plot to help Sarah escape. Mrs. S, Cal, and Paul, who is now a major in the military, confront Marion, the high ranking Dyad official who outranks Rachel and Dr. Leekie, who agrees to release Sarah but stipulates that her safety once released relies solely on herself. Sarah is taken into an examination room to undergo an oophorectomy, and is able to escape Rachel's clutches with Scott's assistance. Scott gives Sarah an access card, and she enters Kira's to find Marion already preparing Kira for departure. Marion tells Sarah to visit her home if she wishes to find out answers to her questions. Sarah, Helena, Alison, and Cosima congregate in Felix's apartment. Helena leaves in the middle of the night and is kidnapped by two men. Sarah visits Marion's home the next day and encounters Charlotte, the last living clone of the 400 attempts that were made to perpetuate Project Leda. Kira shares with Cosima the special book that she was given by Ethan before he was taken to the Dyad Institute. Helena is escorted by the military to a plane as Mrs. S and Paul watch from a distance. Marion reveals key information about the clone experiment.