The focus of extensive research in the area of prostate cancer vaccines has led to the approval of the first therapeutic vaccine by the US FDA, sipuleucel-T. As our understanding of immunotherapy has increased, novel approaches have been investigated that have shown considerable promise. As the field has continued to evolve, questions have arisen regarding the potential role of immunotherapy: which populations of patients are most likely to benefit from immunotherapy and how and when should these therapies be administered? In addition, what are the best tools that can be used as surrogates to monitor immune responses to cancer vaccines that truly can give meaningful insight toward improving clinical outcomes? Finally, how can combination approaches be applied to prostate cancer vaccines in terms of both standard of care and experimental therapies? This review will address many of these important concepts with regard to prostate cancer vaccine therapy.