Activision heeft een persbericht de deur uit gedaan waarin een tipje van de sluier wordt opgelicht over de verhaallijn van Quake 4, welke een voortzetting zal zijn van die van Quake II. Tevens heeft men het eerste officiële screenshot van het spel vrijgegeven. Quake 4 maakt gebruik van de Doom 3 engine en wordt ontwikkeld door Raven Software. Het verhaaltje gaat als volgt:Earth is under siege by an alien race. The Strogg are cybernetic warriors--a mechanical frame and decaying body parts stabilized by flesh consumed in a systematic annihilation of other species and civilizations. In a desperate attempt to survive a Strogg attack on Earth, an armada of Earth's finest warriors is sent to take the battle to the Strogg home planet. Earth's initial assault force is nearly annihilated immediately, but one marine manages to infiltrate the base, bring down their planetary defense systems, and kill the Strogg's collective brain and leader--the Makron. Earth assumed the destruction of the Makron would end it all, but it didn't.

That's where QUAKE II leaves off and QUAKE 4 begins.

The Strogg are quickly regrouping. However, with the Strogg's planetary defenses still destroyed, Earth's forces can deliver a full and final assault. This time, you're not alone. You are Matthew Kane, an elite member of Rhino Squad, and part of Earth's next invasion wave. An army of soldiers are fighting with you and an arsenal of weapons and vehicles are at your disposal in this heroic and epic battle between worlds.