Abstract Important conceptual advances in tumor immunology over the last years have shifted the paradigm from focusing on the malignant cell to the importance of host immune components in the design of successful immunotherapies. The immune system, through sophisticated innate and adaptive immune surveillance mechanisms, inhibits the growth and establishment of tumors. However, despite immune surveillance, tumors still escape and grow, mainly as a result of endowed tumor-induced immunosuppressive circuits. Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are the major components of these regulatory networks that facilitate tumor immune escape and significantly compromise the efficacy of current immunotherapies. A better understanding of the induction, function, and expansion of these powerful regulatory compartments represents a major challenge on the clinical benefit of current treatments and may foster the design of novel cancer immunotherapies.