Metastatic castration resistant prostate cancer (mCRPC) refractory to secondary hormonal treatments such as enzalutamide or abiraterone acetate are the most lethal of prostate cancers. In this setting, many resistance mechanisms exist, driven both through the androgen receptor (AR) and independent of AR. In this resistant setting, more molecular biomarkers are now available to guide treatment selection. Of these, the AR-v7 splice variant of the androgen receptor can guide selection for chemotherapy based on the PROPHECY study. Furthermore, patients with mutations in DNA damage repair genes (particularly BRCA2, CDK12, BRCA1, CHEK2, and ATM) are especially susceptible to PARP inhibitors. PROfound, a recent phase 3 trial of mCRPC patients previously treated with docetaxel randomized to olaparib vs secondary hormonal inhibitors, showed improved progression free survival and ORR for olaparib. Patients with CDK12 loss and microsatellite instability also respond well to pembrolizumab, an immune checkpoint inhibitor. Therefore, given these targeted treatments outside of standard of care options, there is more impetus to perform genomic testing to evaluate for molecular biomarkers for mCRPC patients. This talk highlights these molecular alterations and treatment options in mCRPC.