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Understanding the regulation of the CD8⁺ T-cell response and how protective memory cells are generated has been intensely studied. It is now appreciated that a naive CD8⁺ T cell requires at least three signals to mount an effective immune response: (i) TCR triggering, (ii) co-stimulation and (iii) inflammatory cytokines. Only recently have we begun to understand the molecular integration of those signals and how early events regulate the fate decisions of the responding CD8⁺ T cells. This review will discuss the recent findings about both the extracellular and intracellular factors that regulate the destiny of responding CD8⁺ T cells.