Normal homeostasis of the immune system is controlled by a balance of production and death. During an immune response, homeostasis is disturbed as antigen-presenting cells become activated and promote the clonal expansion of antigen-specific lymphocytes. Shortly after the peak of the response, controlled induction of apoptosis, of both antigen-presenting cells and lymphocytes, restores homeostasis. This process is critical to ensure protective immunity and avoid lymphoid neoplasia and autoimmunity. Here, we will discuss recent developments in the molecular players underlying apoptotic control of immune system homeostasis.