Chronic infection with persistent antigenic stimulation results in the generation of exhausted CD8+ T cells, which are considered defective effector CD8+ T cells, and thus compromises effective immune responses. However, recent studies have illustrated that exhausted CD8+ T cells may be purposely generated and maintained to provide mild immune responses against chronic infection or cancer, which can be safer over a long period of time than strong immune responses. Indeed, a specific population of exhausted CD8+ T cells that behaves similarly to self-renewing stem cells and provides a continuous supply of exhausted CD8+ T cells has been identified, indicating that this population can be considered progenitors of exhausted CD8+ T cells. Furthermore, several ground-breaking studies in the last few years have shed new light on the transcriptional regulatory network governing the generation and propagation of exhausted CD8+ T cells, which involves T cell receptor (TCR) signaling that leads to NFAT-TCF1 (nuclear factor of activated T cells-T cell factor 1) activity followed by activation of the TOX/NR4A axis. Elucidation of the intracellular signaling pathways will help to define the definitive developmental stages leading to exhausted CD8+ T cells, which can be exploited to advance our never-ending battle against cancer. This review will summarize the recent discoveries that have deepened our understanding of the exhaustion program of cytotoxic CD8+ T cells.