The role of the HLA in drug allergy has received particular attention with regard to certain drugs and ethnic groups. The drug hypersensitivity syndrome caused by abacavir is strongly associated with HLA-B*5701, and key structures in the peptide-binding cleft of HLA-B*5701 have been identified that permit non-covalent interaction with this drug. This binding may also occur in so-called empty, non-peptide bearing major histocompatibility complex class I molecules. The binding of abacavir to the F pocket of HLA-B*5701 alters the spectrum of self-peptides that can be presented by this major histocompatibility complex class I molecule. This results in the display of a novel peptide repertoire that appears foreign to the immune system. Memory T cell responses in abacavir-hypersensitive donors are directed against a self-peptide that requires abacavir to efficiently bind to HLA-B*5701. This situation is then analogous to alloreactions with the development of a severe cytotoxic response through the activation of cross-reactive effector memory cytotoxic T cells. The rapidity of onset of the reaction and its intensity may depend upon differences in T cell receptor validity.