Peripheral T cell tolerance is critical in the regulation of immune responses to self antigens, and has implications in the control of autoimmunity, allergic responses and transplant rejection. Here we discuss recent and unpublished data demonstrating that ligation of the cell surface receptor Notch on T cells inhibits immune responses and results in the generation of a regulatory T cell population. Using animal models, we show that prior exposure to antigen can inhibit the response to challenge in an antigen-specific fashion. This inhibition is accompanied by the generation of cells with apparent regulatory capacity and we further show that exposure of T cells to Notch and T cell receptor signals together enhances interleukin 10 production, at least in cell culture systems. We discuss how Notch signalling may integrate with other signals to induce tolerance.