An active immune system is essential for optimizing the results of chemotherapy. Many chemotherapy agents, in turn, promote reactivation of the immune system through three main actions: targeting cancer cells, targeting immune cells, and targeting the host’s physiology. For example, targeting tumor cells can reactivate the immune response by inducing immunogenic cell death, a particular mechanism of cell death that occurs under stressful conditions, capable of inducing an inflammatory response that leads to the maturation of dendritic cells and the release of inflammatory cytokines. Specific chemotherapeutic agents can selectively target immunosuppressive cells and others can activate immune effector cells. As a result, chemotherapy may modify the balance between immune effector cells and immune-suppressive cells in favor of the former. Finally, chemotherapy affects the gut microbiota and induces dysbiosis which, in turn, drives the response to chemotherapy and also to immune checkpoint inhibitors. The adequate knowledge of the many immune effects of chemotherapy, that change on the basis of the drug, the scheduling, and the dose, is a tool not yet rationally used in the design of clinical trials combining chemotherapy and immunotherapy. However, existing data developed in a growing number of tumors show that empirically designed combinations improve the benefits expected by either chemotherapy or immunotherapy. Future studies on combining chemotherapy and immunotherapy, based on solid scientific rationales, will further benefit the cancer care.