This study investigates the mutational landscape of lethal, castrate-resistant prostate cancer (CRPC) by sequencing the exomes of 50 heavily pretreated metastatic CRPCs and 11 treatment-naïve, high-grade localized prostate cancers. The researchers identified low overall mutation rates in CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. They found disruptions in *CHD1*, which define a subtype of ETS fusion-negative prostate cancer, and recurrent mutations in multiple chromatin/histone modifying genes, including *MLL2*. The study also demonstrated that *ETS2*, commonly deleted in CRPC through *TMPRSS2:ERG* fusions, is deregulated through mutation. Additionally, they identified novel recurrent mutations in the *AR* collaborating factor *FOXA1*, which represses androgen signaling and increases tumor growth. The findings provide insights into the mechanisms of AR signaling deregulation in prostate cancer and prioritize candidates for future study.This study investigates the mutational landscape of lethal, castrate-resistant prostate cancer (CRPC) by sequencing the exomes of 50 heavily pretreated metastatic CRPCs and 11 treatment-naïve, high-grade localized prostate cancers. The researchers identified low overall mutation rates in CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. They found disruptions in *CHD1*, which define a subtype of ETS fusion-negative prostate cancer, and recurrent mutations in multiple chromatin/histone modifying genes, including *MLL2*. The study also demonstrated that *ETS2*, commonly deleted in CRPC through *TMPRSS2:ERG* fusions, is deregulated through mutation. Additionally, they identified novel recurrent mutations in the *AR* collaborating factor *FOXA1*, which represses androgen signaling and increases tumor growth. The findings provide insights into the mechanisms of AR signaling deregulation in prostate cancer and prioritize candidates for future study.