Cancer chemotherapy drugs are historically regarded as detrimental to immunity because of their myelosuppressive effects. However, accumulating data suggest that the antitumor activity of conventional cancer chemotherapy results in part from its ability to harness the innate and adaptive immune systems by inducing immunologically active tumor cell death. Additional data broaden the immunologic effect of cancer chemotherapy drugs, demonstrating that some drugs have the ability to disrupt pathways of immune suppression and immune tolerance in a manner that depends on the drug dose, and the timing of its administration in relation to immunotherapy. Understanding the cellular and molecular basis of the interactions between chemotherapy drugs and the immune system will facilitate the strategic development of chemoimmunotherapy treatment regimens that both maximize tumor regression and the antitumor immune response for the long-term clinical benefit of cancer patients.