There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects. ; National Institutes of Health (U.S.). (grant 5U24CA143799) ; National Institutes of Health (U.S.). (grant 5U24CA143835) ; National Institutes of Health (U.S.). (grant 5U24CA143840) ; National Institutes of Health (U.S.). (grant 5U24CA143843) ; National Institutes of Health (U.S.). (grant 5U24CA143845) ; National Institutes of Health (U.S.). (grant 5U24CA143848) ; National Institutes of Health (U.S.). (grant 5U24CA143858) ; National Institutes of Health (U.S.). (grant 5U24CA143866) ; National Institutes of Health (U.S.). (grant 5U24CA143867) ; National Institutes of Health (U.S.). (grant 5U24CA143882) ; National Institutes of Health (U.S.). (grant 5U24CA143883) ; National Institutes of Health (U.S.). (grant 5U24CA144025) ; National Institutes of Health (U.S.). (grant U54HG003067) ; National Institutes of Health (U.S.). (grant U54HG003079) ; National Institutes of Health (U.S.). (grant U54HG003273) ; National Institutes of Health (U.S.). (grant P30CA16672)