When a plane lands in New York City with everyone on board dead, Dr. Ephraim Goodweather, head of the CDC’s Canary Project, and his team are called upon to investigate. Harlem pawnbroker Abraham Setrakian races to the airport, convinced that what looks at first like a mysterious viral outbreak might be the beginning of something infinitely more sinister.

The four survivors begin manifesting strange symptoms, but Eph and Nora's attempt to quarantine them is thwarted as the disinformation campaign begins. Meanwhile, in jail, Setrakian receives a surprise visit from an old - a very old - acquaintance.

Eph and Nora fight to save Captain Redfern's life before coming face-to-face with the horrifying effects of the virus. A spike in rat attacks signals Fet that something inexplicable is happening deep below the city. Released from jail, Setrakian begins his own merciless plan to stop the spread of the disease.

Eph races to safeguard his family, only to learn that Kelly is missing. Dutch reveals her role in Palmer’s plan, and Gus is forced to make a difficult decision about Felix.

Eph investigates Kelly’s disappearance and struggles with what he finds. Dutch pursues a plan to retaliate against Palmer, and Fitzwilliam makes a surprising choice.

Setrakian leads Eph, Fet and Nora in the hunt for the Master’s lair. Left behind at the pawnshop with Mariela, Zack risks his safety for Mariela's sake.

Dutch returns with a plan to broadcast Eph’s warning about the vampiric plague. However, they face a new threat when Eichhorst launches his own attack against the pawn shop. Palmer receives a special visitor, and Gus gears up for the on-coming fight but discovers there’s another mysterious factor involved.

Eph and Fet recon for an all-out assault that Setrakian assures them will finally kill the Master. Gus aligns himself with a strange new force, one that may swing the fight in an unforeseen direction.

Eph concocts a plan to make and distribute a bioweapon. Gus realizes Angel can be an unlikely ally, and Kelly comes after Nora and Zack.

Setrakian and Fet use Fitzwilliam's info to attack the Master. Eph returns to NYC frustrated but energized to go after the one person responsible for killing his friends.

Fet and Quinlan track a convoy carrying their prized nuclear weapon; Eph and Alex search for clues to uncover the Master's plan for the fate of the human race; a familiar enemy traps Dutch, who encounters an old friend as well.

Fet and Quinlan must figure out how to get the nuclear bomb back to New York, while a desperate Eichhorst draws near; love-struck Zack tries to learn more about his new crush, but makes a devastating discovery.