Short peptide fragments generated by intracellular protein cleavage are presented on the surface of most nucleated cells bound to highly polymorphic MHCI molecules. These pMHCI complexes constitute an interface that allows the immune system to identify and eradicate anomalous cells, such as those that harbor infectious agents, through the activation of CTLs. Molecular recognition of pMHCI complexes is mediated primarily by clonally distributed TCRs expressed on the surface of CTLs. The coreceptor CD8 contributes to this antigen-recognition process by binding to a largely invariant region of the MHCI molecule and by promoting intracellular signaling, the effects of which serve to enhance TCR stimuli triggered by cognate ligands. Recent investigations have shed light on the role of CD8 in the activation of MHCI-restricted, antigen-experienced T cells and in the processes of T cell selection and lineage commitment in the thymus. Here, we review these data and discuss their implications for the development of potential therapeutic strategies that selectively target pathogenic CTL responses erroneously directed against self-derived antigens.