Drug hypersensitivity reactions in skin are an immune-mediated phenomenon associated with significant patient mortality and morbidity. Antigen-specific T cells, which have been isolated from the peripheral circulation and target organs of hypersensitive patients, are thought to propagate and regulate the development of clinical symptoms. The investigation of clinical cases with respect to the basic cellular and chemical mechanisms that underpin drug hypersensitivity has resulted in: i) the need to redress some aspects of present immunological dogma; and ii) additional fundamental immunological questions. Thus, the aim of this review article is to summarise present opinion on how and why drugs initiate a pathogenic T-cell response in a small section of the population and subsequently reflect on gaps in basic immunology and where future research might lead.