The story starts with the newly-elected President's assassination, causing the break up of the coalition formed during the expansion of the first game.
The first campaign (dedicated to the UEF (United Earth Federation)) follows Dominic Maddox, a UEF officer who is married to an Illuminate. Maddox fights off Cybran until the UEF Commander he serves declared that all Illuminate are terrorists and orders him on a mission to "round up" the Illuminate from his home city. Maddox refuses, goes rogue, and decides to go on his own campaign to remove his old commanding officer from power. Immediately following the defeat of the UEF Commander, he discovers a portal that leads to Seraphim VII, unlocking the second campaign.
The second campaign (dedicated to the Illuminate) follows Commander Thalia Kael as she fights to restore the Illuminate to their former glory before realising her mistake and turning against her former comrades.
The Cybran campaign follows Ivan Brackman (an experimental genetic composite (clone) of Dr. Brackman and Elite Commander Dostya) who is an old roommate of Maddox, who fights under the direction of Dr. Brackman (who Ivan refers to as "father" while attempting to help his friends).
The final battle takes place on the surface of an ancient planetary terraformer called Shiva Prime. After the battle, Ivan comes to a realisation about Shiva Prime and despite protests from his father, destroys the terraformer.