Activation-induced cell death (AICD) of T cells involves the CD95 receptor/ligand system. T cell activation through the T cell receptor results in expression of the CD95 ligand (CD95L) that acts on CD95 + cells by direct binding and in a paracrine or autocrine fashion. In AIDS, upregulation of CD95L in T cells in accelerated by two viral gene products, HIV-1 Tat and gpl20. The CD95 signaling pathways is, therefore, likely to represent an important road to cell death of the CD4 + T cells in AIDS. Recently, the early events in the CD95 signaling pathway have been identified. A key role hereby plays a receptor-interacting member of the interleukin 1β-converting enzymes (ICE), FLICE, that could be a target for therapeutic intervention. In addition to CD95, the role of other members of the TNF receptor superfamily in AIDS is discussed.