A lethal virus spreads throughout Scotland, infecting millions and killing hundreds of thousands. To contain the threat, acting authorities brutally quarantine the country as it succumbs to fear and chaos. The quarantine is successful. Three decades later, the Reaper virus violently resurfaces in London. An elite group of specialists, including Eden Sinclair, is urgently dispatched into Scotland to retrieve a cure by any means necessary. Shut off from the rest of the world, the unit must battle through a landscape that has become a waking nightmare.

In the year 2043, scavenger James Cole (Aaron Stanford) has been recruited by a team of "Project Splinter" scientists led by physicist Katarina Jones (Barbara Sukowa), to travel back in time to the year 2015, and stop the release of a deadly virus by the enigmatic organization known as the "Army of the 12 Monkeys". In Cole's original time-line, the virus caused a plague that resulted in the death of seven billion humans in the year 2017, and its on-going mutations will mean the eventual end of the human race. In the 2015 time-line, Cole will meet and enlist the help of brilliant virologist Dr. Cassandra "Cassie" Railly (Amanda Schull); the two are brought together because a recording mentioning Cole, that Cassie made after the viral outbreak, is uncovered by Jones in the future time-line, prompting her to select Cole for the mission. Cole will also encounter a seemingly unstable math genius named Jennifer Goines (Emily Hampshire), whose father Cole has been tasked to kill, Cassie's ex-boyfriend Aaron Marker (Noah Bean), and the dangerous high-ranking members of the Army of the 12 Monkeys, "Pallid Man" (Tom Noonan) and Olivia (Alisen Down). In the future time-line, Cole will also have to deal with his best friend José Ramse (Kirk Acevedo), and a man named Theodore Deacon (Todd Stashwick), who leads a brutal pack of scavengers from which Cole and Ramse fled. Meanwhile, Cole and Cassie will try to unveil the identity and whereabouts of the mysterious leader of the Army of the 12 Monkeys, who is only known as "The Witness", and is always one step ahead of them.

Violent animal attacks upon humans are occurring all over the world. Jackson Oz, an American zoologist who offers safaris in Africa, begins to notice the animals' strange behavior and takes it upon himself to solve the reason why before these attacks become more coordinated and ferocious.

After saving the life of the President in Washington D.C., a pair of U.S Secret Service agents are whisked away to a covert location in South Dakota that houses supernatural objects that the Regents, an Authority above and outside any government, have collected over the centuries. Their new assignment: retrieve lost objects called "Artifacts", seemingly harmless items that can possess immense power, and investigate reports of new ones.

Following the death of a witness in a court case, Dr. Lee Rosen leads a team of "Alphas", (advanced human beings) who have number of special skills that makes them a formidable team. As Rosen mentors them and teaches the team to harness their considerable skills, they begin to realize that there are powerful forces behind the courthouse murder, including one of their own.

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