Advances in our understanding of the complex mechanisms of immune regulation and the interactions between tumor cells and the immune system have provided a solid foundation for advancing cancer immunotherapy and have inspired novel therapeutic strategies. Optimizing the effectiveness of immunotherapy will require targeting the antitumor immune response at multiple levels, and this may be achieved through synergistic combinations. Examples include combining two cancer vaccines to achieve a "prime and boost" effect, combining two immune checkpoint inhibitors, combining immunotherapy with targeted agents, or combining immunotherapy with low-dose chemotherapy or radiation. Immune checkpoint inhibitors, such as ipilimumab and nivolumab, will likely play an important role in the future of immunotherapy. The ability to block key pathways by which tumor cells seek to evade or suppress the immune response is critical to realizing the potential of cancer immunotherapy. Other exciting advances include recombinant oncolytic viruses and adoptive transfer of chimeric antigen receptor T cells. However, many challenges remain if durable tumor eradication with minimal toxicity is to be achieved in a broader population of cancer patients.