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.

A secret autopsy demonstrates the bizarre progression of the mystery virus, prompting Jim to make a startling confession. Eph and Nora race to find the father of the youngest victim of the plane tragedy, but someone unexpected beats them to it. Ansel, in the grip of disease, takes desperate measures to protect his family.

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.

Eph and Nora finally see their lethal virus in action. Fet takes the security of Red Hook into his own hands while Dutch and Setrakian set off for Staten Island to question Fitzwilliam, Palmer's former body guard.

The strigoi are evolving, becoming faster. Smarter. Eph struggles to improve his failing bioweapon while trying to work through the emotional fallout of the abduction of his son, Zack. As Setrakian and Quinlan attempt to crack the Lumen's deepest-held secrets, Fet helps a Navy SEAL team in a deadly mission: search for the Master through the underground tunnels of New York.

The Occido Lumen is gone. Stolen. Setrakian and Fet race to recover it. Gus and Angel try to hide a secret houseguest while avoiding a police sweep, and Quinlan's thirst for vengeance is revealed.

The Master's voice proves to be more powerful and potentially fatal than Eph or Dutch anticipated. Fet and Setrakian track down the cargo from the Egyptian vessel and realize they may be in over their heads. Quinlan strikes a deal with the Ancients, but a last minute betrayal proves deadly.