Mechanisms of immunosuppression by CD4(+)CD25(+) suppressor T cells have been addressed using many in vitro and in vivo conditions. However, those studies have not yielded a single mode of action. This review will discuss the mechanisms of suppression, which include the local secretion of cytokines such as TGF-beta and direct cell contact through binding of cell surface molecules such as CTLA-4 on suppressor T cells to CD80 and CD86 molecules on effector T cells. Suppression requires the appropriate colocalization of suppressor and effector T cells in different tissue and may involve the interference with T cell receptor signaling that triggers transcription factors important in regulating effector cell function.