It has long been accepted that the response of T cells to a protein antigen is strongly influenced by parameters governing processing and presentation of the immunodominant epitopes. Recent evidence has suggested, however, that subtle changes in the nature of the ligand itself may also affect the outcome of T‐cell receptor (TCR) ligation, necessitating a re‐evaluation of previously accepted paradigms of T‐cell activation. In particular, activation may no longer be regarded as an all‐or‐nothing event, but appears to involve both quantitative and qualitative dimensions. This revolution in our understanding has emanated from the recent discovery that analogues of immunogenic peptides, so‐called altered peptide ligands (APLs), may elicit a subset of normal activation events, or profoundly influence responses to the wild‐type epitope. As such, the potential offered by APLs for modifying the outcome of deleterious immune responses involved in autoimmunity has not passed unnoticed. Indeed, the design and exploitation of novel reagents based on the structure of auto‐antigenic epitopes has enjoyed some measure of success in the treatment of experimental models of autoimmune disease and holds promise for their exploitation within the clinical arena.