Three years after the Titan Station incident, a radical Unitologist group known as the ' Inner Circle' has begun a reign of violent riots and have been destroying the Marker Test Labs on all major colonies to spread the Necromorph infection.

Ellie left to figure out ways to stop the Markers while Isaac stayed in hiding and quickly regretted breaking it off with Ellie. However, due to the events Isaac had witnessed and Ellie's ambition to stop the Markers, the two broke it off. In that time, Ellie's lost eye was replaced and the two developed a romantic relationship. Isaac and Ellie continued to hide from EarthGov and resided on the New Horizons Lunar Colony, a city found on Earth's moon.

Isaac then escaped with mining engineer Ellie Langford after he destroyed the Marker, resulting in Titan Station's destruction. The Marker built by a delirious Isaac on Titan Station somehow 'activated', resulting in another outbreak of Necromorphs. After the events of Dead Space, EarthGov captured Isaac Clarke and harvested his mind for Marker blueprints in order to revive the Marker program, in which Markers are used to provide resources and power for the Human race.

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