Molecular biomarkers play little role in the current treatment of metastatic castration-resistant prostate cancer (CRPC). The advent of next-generation sequencing (NGS) has enabled the comprehensive molecular characterization of the genomic and transcriptomic landscape of both untreated primary prostate cancer and CRPC. Recent studies demonstrating the feasibility of interinstitution studies obtaining and NGS profiling of metastatic biopsies, targeted NGS approaches applicable to routine formalin-fixed, paraffin-embedded specimens, and NGS approaches applicable to circulating DNA and circulating tumor cells portend near-term adoption of NGS approaches in the management and treatment of CRPC. Important considerations in the clinical implementation of NGS include interpatient and intrapatient heterogeneity, disease progression to neuroendocrine/small cell prostate carcinoma, and incorporation into clinical trial design to demonstrate clinical utility. We review the recent progress in NGS-based characterization of CRPC to understand disease biology and inform on barriers to widespread clinical adoption.