Cancer is managed by surgery, radiation therapy, and systemic drug therapies. Drug therapies include endocrine manipulation, single- or multi-agent chemotherapy, and monoclonal antibody therapy. Targeted small molecules that specifically capitalize on vulnerabilities that map to signaling pathways indispensible for tumor growth and progression are now also a part of the standard of cancer care. More recently, rapidly accumulating data illustrates a critical role for the immune system in the response to chemotherapy, radiation (the abscopal effect), and novel targeted cancer therapies. Integrating immune-based therapies strategically with established and novel cancer therapeutics should generate a robust antitumor effect that takes advantage of the strengths of their individual modes of action and also leverages potential immunologic synergies.