Tumor escape from the immune system hampers effective immunotherapy for cancer. Recent evidence indicates that in cancer patients the altered activities of 2 innatelike ("natural") immunoregulatory T-cell populations could prevent the establishment of effective antitumor immune responses. These are CD4+ CD25+ (natural) regulatory T cells and invariant natural killer T cells, which normally play critical roles in orchestrating immune responses to self and nonself. Therapeutic modulation of these regulatory T-cell populations is clinically feasible and will potentially allow the induction of effective antitumor immune responses when combined with currently available immunotherapeutic strategies.