After being offered a recording deal by Rick Rubin's Def Jam Recordings, the band signed and quickly began working on its third album with Rubin as co-producer. The result, 1986's Reign in Blood, has been called a "thrash metal masterpiece" and even credited with almost single-handedly inspiring the entire death metal genre, at least in North America.

Kerrang! called Reign in Blood as "the heaviest album of all time". In 2003 Slayer played the album in its entirety throughout their fall tour (something they never did on the original album tour). A DVD of one of these performances was released with the title Still Reigning. Closer "Raining Blood" culminated with the band being drenched in a rain of fake blood. In 2006 Metal Hammer named Reign In Blood their number one of their top two hundred albums in Metal Hammer's lifetime. It also came in at number one in their top twenty thrash albums.

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