Regulatory T cells (Tregs) are an immunosuppressive T cell subset that functions to prevent autoimmunity and to regulate physiologic immune reactions. Tregs are also present in the tumor microenvironment and appear to play an important role in the pathophysiology of malignant processes. Available data suggests that this role is context-dependent, as a higher density of tumor infiltrating Tregs at diagnosis may be associated with either a positive or a negative clinical outcome. Negative prognostic associations are found primarily in solid tumors such as ovarian carcinoma, while positive associations have been reported in various lymphomas, most prominently in those of germinal center (GC) B cell derivation. Most of these observations are correlative, however, as mechanistic studies have lagged behind descriptive observations because of a lack of informative animal models. Nonetheless, the available data are intriguing and provide compelling support for the hypothesis that Tregs are pathobiologically relevant. This review focuses on studies of the role of CD4 (+)CD25 (+)FOXP3 (+) Tregs in hematopoietic malignancies and clonal myeloid neoplasms.