Clinicians had suspected for years that drug eruptions were probably mediated by immune mechanisms because their timing suggested sensitization and specific immunologic memory rather than direct toxicity. An immune response to medications was also demonstrated by positive skin tests and by several types of in vitro tests that evidenced immediate or delayed hypersensitivity. In the last decade several teams of researchers obtained in vitro drug-specific human T-cell clones, in a variety of clinical types of drug eruptions. These clones were produced from blood or skin mononuclear cells of patients with a history of drug reaction by stimulation in vitro with drug. They were either of CD4 or CD8 phenotypes. Drug specific clones were stimulated by the parent drug much more often than by reactive metabolites. That challenged the classical "hapten hypothesis" that the immune response was initiated by reactive metabolites combined to self proteins. The medication usually stimulated specific T-cells after non-covalent binding to major histocompatibility (MHC) molecules on antigen presenting cells. In toxic epidermal necrolysis, T-lymphocytes present at the site of lesions, exhibited a drug specific cytotoxicity against autologous target cells, or allogeneic cells that shared the same HLA than autologous cells. This MHC class I restriction and mediation of death by perforin/granzyme release, is the classical behavior of cytotoxic T lymphocytes, like those operating in the reject of a transplanted organ. MHC restriction could explain the key role of HLA genes as predisposing factors to severe drug reactions. A strong association between HLA and hypersensitivity to abacavir, SJS or TEN to carbamazepine or allopurinol has been recently demonstrated. Resemblance to graft rejection points to the possible therapeution value of immuno suppressive agents. Most drug eruptions appear to result from T-cell mediated delayed hypersensitivity. The secondary activation of different cascades of cytokines, may contribute to the heterogeneity of clinical presentations.