Recognition of peptide / MHC complexes by TCR is a highly sensitive interaction. Even subtle changes in the index peptide amino acid sequence can drastically alter T cell responses. Such peptide variants or analog peptides are termed altered peptide ligands (APLs). Some APLs can act as partial agonists, as they induce only some T cell effecter function but not others, such as cytokine secretion, proliferation or cytolysis. Other APLs, so-called antagonists, inhibit subsequent T cell responses to the index peptide, when presented on the same antigenpresenting cell (APC) as haeindex peptide. Naturally occurring APLs have first been observed in viral diseases (HBV, HIV), and more recently in a number of other diseases. The mechanism of APL antagonism is not fully understood. Inhibition of protective T cell responses by APL antagonism represents a powerful means for immune evasion, not only by pathogens but also in cancer. Inhibition of auto reactive T cell responses by APLs, on the other hand, can provide a new strategy for the treatment of autoimmune diseases. This review will discuss the relevance of APL antagonism in infectious diseases, in autoimmunity, in cancer and the mechanism of APL antagonism.