Homeostasis within the immune system is complicated by the need to selectively force the survival of potentially useful lymphocytes in the central lymphoid organs and of antigen-reactive cells in the periphery. Coupled with this requirement, is the need to delete strongly autoreactive cells in the thymus and bone marrow and downsize the foreign antigen-reactive cells following elimination of the pathogen. Homeostasis is achieved by coupling the fate of the cell to the integration of signals received through the antigen receptor, co-stimulatory receptors and cytokine receptors as well as members of the tumor necrosis factor receptor family that are highly specialized to promote survival or death of a cell. In this review, we briefly discuss how well-defined pathways that promote cell survival PI-3 kinase, Akt, Bcl-2 family and inhibitors of apoptosis (IAPs)-function within the cell. We discuss how cell death stimuli signal either the intrinsic, mitochondrial pathway of apoptosis or kill the cell through one of the six death receptors such as Fas (APO-1/CD95). Finally, the consequences of spontaneous and genetically engineered mutations within survival and death pathways are discussed in the context of predisposition to autoimmune disease and cancer.