Naturally occurring CD25⁺CD4⁺ regulatory T cells (T_R cells), which specifically express the transcription factor Foxp3, engage in the maintenance of immunological self-tolerance and suppressive control of aberrant or excessive immune responses to foreign antigens. They may, on the other hand, impede immune surveillance against cancer and hamper the development of effective immunity to autologous tumor cells. Indeed, natural T_R cells have been observed to predominantly infiltrate tumor masses especially in the early phase of tumor progression. Depletion of natural T_R cells by removing CD25⁺ T cells prior to tumor challenge is therefore able to provoke effective tumor immunity in animals. Furthermore, attenuation of T_R cell-mediated suppression in on-going anti-tumor immune responses, for example by altering signaling through CTLA-4 or GITR expressed by natural T_R cells, can enhance the responses and thereby eradicate advanced cancers. A combination of depletion or attenuation of T_R cells and concomitant stimulation of effector T cells, systemically or locally in tumors, may be a feasible immunotherapy for cancer.