African-American men have the highest incidence of and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (<i>n</i> = 102) and targeted validation (<i>n</i> = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in <i>ERF</i>, an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed <i>ERF</i> deletions in 3% of primary prostate cancers and mutations or deletions in <i>ERF</i> in 3% to 5% of lethal castration-resistant prostate cancers. Knockdown of <i>ERF</i> confers increased anchorage-independent growth and generates a gene expression signature associated with oncogenic ETS activation and androgen signaling. Together, these results suggest that <i>ERF</i> is a prostate cancer tumor-suppressor gene. More generally, our findings support the application of systematic cancer genomic characterization in settings of broader ancestral diversity to enhance discovery and, eventually, therapeutic applications.<b>Significance:</b> Systematic genomic sequencing of prostate cancer in African-American men revealed new insights into prostate cancer, including the identification of <i>ERF</i> as a prostate cancer gene; somatic copy-number alteration differences; and uncommon <i>PIK3CA</i> and <i>PTEN</i> alterations. This study highlights the importance of inclusion of underrepresented minorities in cancer sequencing studies. <i>Cancer Discov; 7(9); 973-83. ©2017 AACR.</i><i>This article is highlighted in the In This Issue feature, p. 920</i>.