CD4+CD25+FOXP3+ regulatory T cells (Tregs) are elevated in cancers and can thwart protective antitumor immunity. Recent human cancer trials suggest that depleting Tregs can be clinically beneficial. Additional types of deleterious regulatory cells are also increased in cancer. Tregs also play unanticipated roles in cancer therapy in that some drugs unexpectedly increase (e.g. cancer vaccines or IL-2 treatment) or decrease (e.g. antineoangiogenesis agents or receptor tyrosine kinase inhibitors) their numbers or function. Managing deleterious effects of regulatory cells represents a novel and potentially effective way to give immunotherapy for cancer. New insights into molecular mechanisms governing trafficking, differentiation, and function of these cells suggest novel approaches to manipulating them as treatment strategies.