Using cells from TCR transgenic mice that do or do not express Fas, we show that there are two mechanistically distinct forms of apoptosis in CD4⁺ T cells. Naive T cells undergo apoptosis if cultured in the absence of antigen or costimulation. This form of programmed cell death (PCD) is not dependent on Fas, and is prevented by CD28-mediated signals, which lead to the secretion of growth factors and the expression of survival genes, such as bcl-x_L. Recently activated T cells undergo apoptotic death upon repeated stimulation. This activation-induced cell death (AICD) is mediated by Fas, but is independent of costimulation and is not prevented by IL-2 or bcl-x_L. Finally, we show that peripheral tolerance may be induced in vivo independent of Fas-mediated cell death.