Indoleamine 2,3-dioxygenase (IDO) is a natural mechanism of creating acquired tolerance in a variety of physiological settings. This endogenous tolerogenic pathway has important functions in regulating the magnitude of immune responses in settings of infection, pregnancy, tissue transplantation, mucosal interfaces and others. Whether for angiogenesis, stromal formation or immunologic tolerance, tumors often rely on recruiting host mechanisms. IDO is one such potent endogenous mechanism that appears to be frequently hijacked by tumors to establish systemic immune tolerance to tumor antigens. IDO can be expressed by tumors themselves, but, in addition, its natural site of expression is the host immune cells recruited by the tumor (particularly dendritic cells and macrophages). Therapeutic strategies that target the IDO pathway have been shown to synergize with standard chemotherapy and experimental immunotherapies to break tumor-induced tolerance. When such strategies target IDO expressed in host cells, they may be able to disrupt tolerance without creating intrinsic tumor cell drug resistance.