Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%–60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals. Display omitted •A multi-institutional integrative clinical sequencing of mCRPC•Approximately 90% of mCRPC harbor clinically actionable molecular alterations•mCRPC harbors genomic alterations in PIK3CA/B, RSPO, RAF, APC, β-catenin, and ZBTB16•23% of mCRPC harbor DNA repair pathway aberrations, and 8% harbor germline findings A multi-institutional integrative clinical sequencing analysis reveals that the majority of affected individuals with metastatic castration-resistant prostate cancer harbor clinically actionable molecular alterations, highlighting the need for genetic counseling to inform precision medicine in affected individuals with advanced prostate cancer.