The improved survival with sipuleucel-T, an autologous antigen-presenting cell–based agent, for the treatment of patients with metastatic asymptomatic and minimally symptomatic castration-resistant prostate cancer supports immunotherapy as a valid approach. Also, multiple novel immunotherapeutic approaches are undergoing vigorous investigation. T-lymphocyte checkpoint blockade and poxvirus-based prime-boost approaches are in phase III evaluation. Other immunotherapeutic platforms undergoing early investigation include radioimmunoconjugates and adenovirus-based, DNA-based, and Listeria-based approaches. The development of predictive markers for immune response that translate into improved long-term outcomes is important. This article reviews the emerging data and the unique strengths and weaknesses of these approaches.