Clinical trials involving T cell-based immunotherapy for the treatment of human cancer have shown limited degrees of success. In cancer vaccine trials conducted at multiple centers worldwide, immunization has often resulted in the robust elicitation of T cells that specifically recognize antigens expressed on the surface of tumor cells. However, to date, objective clinical responses resulting from these approaches have remained relatively rare. By contrast, adoptive transfer of laboratory-expanded T cells into patients has had more success, producing impressive clinical regressions in a subset of advanced metastatic melanoma patients. The failure of activated T cells to consistently induce clinical responses in many other patients has pushed us toward a deeper understanding of natural immunoregulatory mechanisms that are directly responsible for diminishing tumor-specific T-cell activation, migration, and effector function in vivo. Such immunosuppressive factors likely evolved to prevent autoimmunity, but are frequently co-opted by tumors to evade tumor-specific immune responses. With this knowledge, it now becomes imperative to develop specific clinical interventions capable of eliminating tumor-specific immunosuppression, with the goal of shifting the balance to favor effector T-cell function and tumor cell killing.