The goal of vaccine-based cancer immunotherapy is to induce a tumor-specific immune response that ultimately reduces tumor burden. However, the immune system is often tolerant to antigens presented by the tumor, as the cancer originates from within a patient and is therefore recognized as self. This article reviews selected clinical strategies for overcoming this immune tolerance, and approaches to enhance generation of immunity to tumor-associated antigens by activating innate immunity, potentiating adaptive immunity, reducing immunosuppression, and enhancing tumor immunogenicity. Success in the field of cancer vaccines has yet to be fully realized, but intelligent choice of immunomodulators, tumor antigens and patient populations will likely lead to clinically relevant uses for cancer vaccines.