FOXP3+ CD25+ CD4+ regulatory T (Treg) cells, crucial for the maintenance of immunological self-tolerance, are abundant in tumors. Most of them are chemo-attracted to tumor tissues, expanding locally and differentiating into a Treg-cell subpopulation that strongly suppresses the activation and expansion of tumor-antigen-specific effector T cells. Several cancer immunotherapies targeting FOXP3+ CD4+ Treg cells, including depletion of Treg cells, are currently being tested in the clinic. In addition, clinical benefit of immune-checkpoint blockade, such as anti-CTLA-4 monoclonal antibody therapy, could be attributed at least in part to depletion of FOXP3+ CD4+ Treg cells from tumor tissues. Thus, optimal strategies need to be established for reducing Treg cells or attenuating their suppressive activity in tumor tissues, together with activating and expanding tumor-specific effector T cells.