Genesis takes place sometime before the events of the first game and introduces the fourth Horsemen, Strife, a gun-wielding wise-cracker. The general setup is that Strife and his brother War (protagonist of the first Darksiders game) are tasked by the enigmatic Charred Council to help "maintain the balance" by figuring out what ole Lucifer is up to and why he's empowering some demons. That's tipping the scales, Luci! So Strife and War set out to talk to Samael and see what he knows; thus, the stage is set and you'll progress through 16 more levels to unravel the mysteries.
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Genesis is a prequel to the events depicted in the other three Darksiders games. The Apocalypse hasn't kicked off just yet and you're still working for the enigmatic Council (of giant talking heads). As Strife, you are tasked with maintaining "the Balance" by investigating why that wily ole Lucifer is giving his "master demons" a totally natural boost of "supplements" to make them beefier than usual. You're joined in this adventure by War and can switch between them, unless you've got a buddy along for the ride in which case they can play as War while you are Strife.