After her inauguration, newly elected Vice President Natalie Maccabee is initiated into a covert world of danger by her chief steward, Malcolm Millar and Chief Justice Caleb Thorne. Contrary to what the public believes, the job of Vice President is far from ceremonial. In fact, enshrined in a secret version of the Constitution is a section endowing Natalie with her own secret agent, John Case, to be deployed in times of crisis. Natalie quickly finds herself in play when the daughter of FBI Director Stanton is kidnapped, and authorities are helpless in rescuing her.

One of John's old nemeses steals an arsenal of nuclear warheads and a scientist to activate them. John is forced to work with his enemy, Olga Petrovka, in order to destroy them and rescue the scientist. Natalie and Malcolm endeavor to protect John's identity from an FBI investigation.

John breaks the protocol of the Agent X Brotherhood to protect a former lover from members of a Washington D.C.- based cabal intent on taking down the President. Natalie, Malcolm and Judge Thorne work to unmask the members of the conspiracy.

The cabal trail leads John to a lawless Mexican town, where he is drawn into a deadly feud between the local drug lord, nicknamed El Diablo, and the town's police chief, Luna. At the same time, Natalie probes into a romantic connection between her late husband, Steven, and the fiancé of her political adversary, Speaker of the House Miles Latham.

A biological weapon is used in a failed assassination attempt on a high ranking government official. John, Natalie and Malcolm investigate the case and quickly find themselves racing the clock to stop a domestic terrorist group from deploying the virus on a greater, catastrophic scale.

John, incognito as a Secret Service Agent, accompanies Natalie on clandestine peace talks between the Mexican government and Marxist insurgents. When their helicopter is shot down by nefarious forces, the group is suddenly stranded in the middle of nowhere, hunted by some of the most dangerous men in the world.

John wakes up in an Odessa basement, imprisoned by an unexpected captor; Malcolm works desperately to find and rescue John.

John travels in disguise to a party on a billionaire's island in hopes of stealing a dangerous, high-tech weapon; Natalie struggles to contain the fallout from the conspiracy against the President.

A terrorist blackmails John into going on a suicide mission.

John tries to rescue Natalie, Eckhart and international leaders from a hostage crisis in an opera house in Paris.