Resting mature T-lymphocytes are activated when they are triggered via their antigen-specific T-cell receptor (TCR) molecule or the associated CD3 antigen. In contrast, preactivated T-cells can undergo activation-induced cell death (AICD) in response to the same signals. Stimulation of activated T-cells upregulates the expression of the Fas-ligand, and the interaction of Fas-ligand with the corresponding Fas receptor triggers an apoptosis program that culminates in cellular suicide usually associated with the fragmentation of DNA into oligonucleosomal bands. Molecular evidence indicates that proteases related to interleukin-1-beta converting enzyme play an essential role in the execution of cell death. AICD of mature T-lymphocytes can be efficiently triggered by monoclonal antibodies against the CD3/TCR complex, or by superantigens such as bacterial enterotoxins. Although it is more difficult to induce AICD by conventional peptide antigens, it is now clear that antigen-induced AICD is a powerful means of eliminating antigen-reactive T-cells. Therefore, AICD contributes to the regulation (i.e., termination) of cellular immune responses. In addition, AICD might play a role in the establishment of peripheral immune tolerance. Increased knowledge of the molecular mechanisms of AICD opens new immunotherapeutical perspectives for the treatment of certain autoimmune diseases, and will have implications in other areas such as transplantation medicine.