The role of death receptors and caspases as mediators of programmed cell death is well established. This review focuses on new insights into alternative functions of these molecules in activation and proliferation of lymphocytes and other hematopoietic cell types. The involvement of the death receptor Fas and caspases in immunodeficiency and autoimmunity is discussed. Elucidation of the mechanisms that control the decision whether death receptors and caspases drive activation/proliferation or apoptosis may broaden our knowledge about the pathogenesis of numerous diseases and facilitate the development of novel therapeutic strategies.