The host immune system is required for sustained tumor regression following oncogene withdrawal. Following oncogene inactivation in a mouse model by transgenic methods or in patients by oncogene-targeted therapy, there are tumor cell-intrinsic consequences, immunological consequences, and host microenvironmental consequences. Tumor cell-intrinsic consequences include proliferative arrest and the induction of apoptosis. Dying tumor cells and antigen debris may stimulate an immune response, which may in turn feed back in to the tumor cell-intrinsic consequences. The immune response, particularly helper T cells, can influence environmental consequences, including the induction of senescence and the collapse of angiogenesis. Lastly, senescing tumor cells may have a secretory phenotype, which in turn may influence the immune system. Taken together, these three components lead to a remodeling of the entire tumor (both in the cancer cells and in the environment) and contribute to lasting tumor regression and protection from relapse.