Notch signalling plays a critical role in embryogenesis, influencing the differentiation and growth of a variety of cell types across the species. In the mammalian immune system, Notch signalling operates at various levels; it controls the differentiation of haematopoietic stem cells and directs the early development of the T and B-cell lineages. It is also involved in the maturation of both CD4+ and CD8+ T cells in the thymus. The biological activities of this pathway extend beyond lymphocyte ontogeny; recent evidence has shown that it also contributes to the regulation of the peripheral immune system through its ability to influence cell survival and growth. In fulfilling this function, Notch signalling appears to act in conjunction with defined immunological signals such as cytokines, T-cell antigen receptor and co-stimulatory receptor-mediated signalling. In this review we discuss the potential of the Notch signalling pathway in the maintenance of homeostasis within the immune system affecting both peripheral tolerance and the negative feedback controlling productive immunity. The therapeutic manipulation of this pathway is likely to have broad application in a range of immunologically based diseases.