Programmed cell death (PCD) is a necessary process that helps to regulate the lifespan of lymphocytes and maintain the compartmental balance of lymphoid organs. In addition, PCD is required for the generation and maintenance of self-tolerance. Strategies that inhibit PCD cause profound alterations in the (patho)physiology of the immune system. Here, Guido Kroemer and Carlos Martínez-A. discuss the multiplicity of PCD-inducing pathways, which have been revealed through the use of PCD-inhibitory agents, and analyse the levels at which these agents act.