Following an emotional breakup, tough but tender FBI super-agent Will Chase (code name: "Whiskey Cavalier") is assigned to work with badass CIA operative Frankie Trowbridge (code name: "Fiery Tribune"). Together, they must lead an inter-agency team of flawed, funny and heroic spies who periodically save the world - and each other - while navigating the rocky roads of friendship, romance and office politics.
The Whiskey team is sent to Prague for their first official mission where Will has to seduce the widow of a notorious shipping tycoon in order to gain access to a list of criminal clients, but Frankie doubts his ability to deceive a grieving woman. Back in New York, the bureau assigns the team a new liaison, who just so happens to be the last person Will wants to see.
Will and Frankie continue to clash, and their growing pains may jeopardize the team's next mission in Rome where they are sent to prevent a terrorist attack.
While investigating suspicious robberies in London, Will hits it off with a sexy British spy, leaving Frankie with some unexpected feelings that she doesn't know how to process. Meanwhile, Jai competes with Susan over who is more intelligent, and Standish deals with a case of shell shock.
The team heads to Europe to transport a dangerous prisoner for interrogation, and the prisoner is Will's former boss; Jai helps organize a Secret Santa gift exchange for an off-season Spy Christmas.
Frankie is forced to prove herself when Will is captured during a mission to take down an organ harvesting operation; Will spends his time in captivity trying to bond with Jai; Standish seeks Frankie's help to improve his combat skills.
Ollerman attempts to force the team to commit a terrorist attack for The Trust using Ray’s life as leverage. Meanwhile, Jai helps Standish deal with a revelation about Tina, and Will and Frankie come to a realization about their relationship.