Various molecular mechanisms have been implicated in the progression from hormone-sensitive to castration-resistant prostate cancer (CRPC). Novel targeted agents to treat CRPC have been developed that inhibit either androgen receptor (AR)-mediated signaling (AR antagonists and inhibitors of androgen synthesis) or non-AR-mediated signaling (inhibitors of Src, mammalian target of rapamycin, chaperone proteins, insulin-like growth factor-1 receptor, vascular endothelial growth factor, and endothelin-A receptor) pathways. However, variable efficacy has been observed in clinical trials, most likely because of the biologic heterogeneity of CRPC. To account for potential differences in disease biology, a more individualized approach to treatment, based on genomic and/or proteomic analyses of individual tumors, is being investigated. By identifying tumors with a characteristic molecular subtype and assigning treatment accordingly, it is hoped that a higher proportion of patients will benefit from targeted therapy. Additionally, lessons learned through the application of these technologies to prostate cancer may subsequently influence therapeutic development in other solid tumors.