The immune system balances effector responses with tolerance, to protect the host from pathogens while minimizing local damage to tissue. An altered control of immune homeostasis can lead to loss of tolerance to self antigens in autoimmunity, or promote unwanted tolerance to tumor growth. This review focuses on the dual activity of CD4(+) regulatory T cells (Tregs) in autoimmunity and cancer. Tregs play a key role in the mechanisms of immune tolerance and actively suppress pro-inflammatory responses, thus providing a beneficial action in autoimmunity and detrimental effects in cancer.