Summary: The loss of CD28 expression on T cells is the most consistent biological indicator of aging in the human immune system, and the frequency of CD28null T cells is a key predictor of immune incompetence in the elderly. There is also mounting evidence for the high frequency of these unusual T cells among patients with inflammatory syndromes or with chronic infections disproportionate with their age. In these pathological states, CD28null T cells likely represent prematurely senescent lymphocytes due to persistent immune activation. Unlike the situation in CD28 gene knockout mice that have anergic CD280/0 T cells, human CD28null T cells are functionally active, long-lived, oligoclonal lymphocytes that lack or have limited proliferative capacity. Results of replicative senescence studies show that CD28null T cells are derived from CD28+ precursors that have undergone repeated stimulation, indicating that CD28 silencing underlies the program of T-cell aging. Dissection of the machinery regulating CD28 expression is paving the way in elucidating the molecular events leading to immune senescence as well as providing clues into the functional rejuvenation of senescent T cells.