Many of the tumour antigens targeted by active immunisation strategies are in fact self-antigens. Successful anticancer immunotherapy will therefore require not only potent methods of T cell activation, but also successful interference with mechanisms of immune tolerance that have evolved to prevent tissue destruction by autoreactive T cells. In addition to thymic deletion, anergy and skewing of T cell cytokine expression, a role for immunoregulatory T cells in the maintenance of self-tolerance has been suggested. Suppression of autoreactive T cells by regulatory T cells has been suggested to occur by both cytokine and cell-contact-dependent mechanisms. In murine models, suppression of auto-reactive T cells mediated by cell contact has been attributed to a population of spontaneously occurring CD4+CD25+ T cells. Cells with similar phenotype and function have been found in healthy humans. In murine models, these cells behave as regulatory T cells, counteracting autoimmune and inflammatory reactions, and have a role in tolerance and in peripheral T cell homeostasis. Of interest for cancer immunotherapy is the fact that depleting these cells results in the induction of antitumour immune responses, particularly after tumour specific vaccination. One hypothesis is that depleting these CD4+CD25+ counter-regulatory T cells in humans with cancer will enhance the efficacy of anticancer immunisations.