A basic principle of immunology is that lymphocytes respond to foreign antigens but tolerate self tissues. For developing T cells, the ability to distinguish self from non-self is acquired in the thymus, where the majority of self-reactive cells are eliminated. Recently, however, it has become apparent that some self-reactive T cells avoid being destroyed and instead differentiate into specialized regulatory cells. This appears to be beneficial. Subpopulations of self-reactive T cells have a strong influence on self tolerance and may represent targets for therapeutic intervention to control a variety of autoimmune diseases, tumour growth and infection.