6 months have passed since the events of Conviction. Sam Fisher and Victor Coste are leaving Andersen Air Force Base when it suddenly comes under attack by a group of heavily armed terrorists. With the help of hacking specialist Charlie Cole, Sam and Vic manage to escape, but Vic gets hurt shielding Sam from a grenade explosion.

Not long after, a group called "The Engineers" take responsibility for the attack and announces the start of "The Blacklist" - a countdown of deadly attacks on high value U.S. assets that will be carried out unless the U.S. Government withdraws all troops deployed abroad. US President Caldwell assigns Sam Fisher, Cole, Isaac Briggs and Anna Grímsdóttir to a new special ops & counter-terrorism unit called "Fourth Echelon". Charged with stopping The Engineers, the team uses the "Paladin" cargo plane as a command center and initiate highly sophisticated missions to hunt down and exterminate the terrorists.