Men with metastatic castration-resistant prostate cancer have multiple treatment options, and the expanding palate of available therapies renders careful patient selection imperative. Men with visceral (especially hepatic) metastases have a particularly poor prognosis, regardless of the treatment selected. Retrospective analyses of datasets from large phase III randomized trials showed that men with visceral metastases appear to derive clinical benefit from second-generation antiandrogens as well as from docetaxel chemotherapy, but not from immunotherapy. The mechanistic underpinnings of these observations are currently not clear, but could involve factors that are intrinsic to the tumor cell, the tumor microenvironment, and/or systemic factors. Regardless of the underlying mechanism(s), a better understanding of the basic biology of visceral vs bone metastases will be critical in improving prostate cancer treatment in the setting of advanced disease.