Chemotherapy directly targets the transformed tumor cell, and has long been a key component of therapy for most early and advanced cancers. However, its utility is ultimately limited by unavoidable toxicity to normal tissues, and by drug resistance pathways deeply embedded within the biology of the tumor cell itself. These limitations strongly argue for innovative strategies to treat and manage cancer. Engaging the power of the patient's own immune system is a highly attractive way to complement the activity of standard cancer treatment. Tumor vaccines offer the potential for preventing cancer in those at high risk for disease development, preventing relapse in those diagnosed with early cancer, and treating advanced disease. Notably, the barriers to tumor vaccine efficacy are distinct from the limitations of combination chemotherapy. The ability of vaccines to induce a response robust enough to mediate tumor rejection is limited by the extent of disease burden, the suppressive effect of the local tumor micronenvironment, and multiple layers of systemic immune tolerance established to keep the immune response turned off. Chemotherapy can be used with tumor vaccines in unexpected ways, breaking down these barriers and unleashing the full potential of the antitumor immune response.