RECEPTOR crosslinking of T-cell hybridomas induces cell activation followed by apoptosis(1-6). This activation-induced cell death requires de novo synthesis of RNA and proteins(1-3), but the actual gene products that provide the death signal have not been identified(4-6). We show here that receptor crosslinking induces Fas ligand and upregulates Fas, and that the ensuing engagement of Fas by Fas ligand activates the cell-death programme. Cell death, but not activation, can be selectively prevented by a soluble Fas-immunoglobulin fusion protein. Thus, Fas and Fas ligand are the death-gene products, and their interaction accounts for the molecular mechanism of activation-induced T-cell death.