Expansion of CD8⁺ lymphocyte subsets are found in many states with chronic antigenic exposure including HIV, multiple myeloma, rheumatoid arthritis, CMV infection, transplantation and even normal aging. These expansions are characterized by the expression of CD57 antigen and the loss of CD28^-. These lymphocytes are thought to represent clonally expanded cytotoxic T lymphocytes (CTL) that have become senescent and lack proliferative ability. These cells also demonstrate suppressive properties and have been linked with immunodeficiency raising the question of the function of these cells in relationship to immunoregulation. Alterations in the CD95/Fas apoptotic pathway and changes in pro-survival factors such as Hsp27 likely contribute to this lymphocyte subset expansion. Further understanding of the normal CD8⁺ lymphocyte response to antigen and the factors that lead to abnormal continued expansion in certain disease states will be crucial to understanding the pathogenesis of chronic antigenic stimulation.