Comprehensive identification of driver mutations in prostate cancer can serve to enhance our understanding of the disease and expand the use of available treatment options. Two recent and complementary studies from Barbieri et al.1 and Grasso et al.2 have reported the results of exome sequencing analysis in large cohorts of primary, treatment-naïve and lethal castration-resistant prostate cancer (CRPC) cases, respectively. Together, these analyses revealed a number of novel genetic mutations representing uncharacterized drivers as well as combinations of mutations that may define important prostate cancer subtypes.