After years of banishment from mainstream immunology, the notion that one subset of T cells can exert regulatory effects on other T lymphocytes is back in fashion. Recent work in knockout and transgenic mice has begun to bring molecular definition to our understanding of immunoregulatory CD4+CD25+T cells (Treg/Th3/Tr1). The identification of the glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18) expressed on T regulatory cells might afford new therapeutic opportunities. Another possible therapeutic intervention could be the blockade of signaling through the molecular pair of tumor necrosis factor-related activation induced cytokine (TRANCE) and receptor activator of NF-&kgr;B (RANK). Based on the available evidence from experimental mouse tumor models, however, it seems that simply blocking or even eliminating T regulatory function will not be enough to manage established tumors. The challenge for immunotherapists now is to overcome immunosuppression using the knowledge gained through the understanding of T regulatory cell function.