Metastatic castration-resistant prostate cancer (mCRPC) is considered as the final stage of the disease with limited therapeutic options to date. In this article, we review recent histopathologic and molecular pathologic findings that may expand our understanding of the disease and may lay, or have already laid the groundwork for the development of novel and individualized therapies. These include the detection of pathogenic mutations in the DNA repair genes BRCA1/2, androgen receptor splice variant 7 (AR-V7), deletion of the tumor suppressor gene PTEN, and evidence of neuroendocrine prostate cancer (t-NEPC) arising under antiandrogenic therapy. The theoretical and diagnostic basis behind the increasing relevance of pathology for therapeutic guidance in this stage of disease are presented.