A wealth of data indicates that tumor immunity directed against a wide variety of malignancies is suppressed in cancer patients. Recent studies have explored the role of ‘natural’ CD4⁺CD25⁺ regulatory T cells (Tregs) in the suppression of tumor immunity in cancer patients. It is now clear, using multiple phenotypic and functional criteria, that the frequency of Tregs is increased in the peripheral blood of cancer patients as well as within the tumor microenvironment. Human Tregs with specificity for tumor-associated antigens have recently been identified, and murine studies have demonstrated that vaccination with tumor-associated antigens can expand Tregs, posing a challenge to cancer vaccine strategies. However, a variety of approaches, including depletion of Tregs or modulation of their activity in vivo, might soon enhance the efficacy of existing cancer vaccines directed against a variety of malignancies.