Human peripheral blood CD8⁺ T cells comprise cells that are in different states of differentiation and under the control of complex homeostatic processes. In a number of situations ranging from chronic inflammatory conditions and infectious diseases to ageing, immunodeficiency, iron overload and heavy alcohol intake, major phenotypic changes, usually associated with an increase in CD8⁺ T cells lacking CD28 expression, take place. CD8⁺CD28^– T cells are characterized by a low proliferative capacity to conventional stimulation in vitro and by morphological and functional features of activated/memory T cells. Although the nature of the signals that give origin to this T‐cell subset is uncertain, growing evidence argues for the existence of an interplay between epithelial cells, molecules with the MHC‐class I fold and CD8⁺ T cells. The possibility that the generation of CD8⁺CD28^– T cells is the combination of TCR/CD3ζ‐ and regulatory factor‐mediated signals as a result of the sensing of modifications of the internal environment is discussed.