Notch signaling regulates many cell fate decision and differentiation processes during embryonic development and tissue homeostasis. Moreover, disregulation of the pathway is associated with human disorders and cancer. In the last 15 years it became evident that Notch plays important roles in the hematopoietic system as well as in the regulation of immune responses. This special issue on Notch regulation of the immune system summarizes recent advances and covers multiple aspects of Notch signaling within the hematopoietic and the immune system. This issue covers subjects including Notch function in embryonic and adult hematopoietic stem cells, lymphocyte development and function as well as in T cell leukemia.