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Defining predisposition to allergic drug reactions has largely focussed on HLA associations, but other genetic and nongenetic factors are also likely to be involved.Polymorphic genetic variants in cytokine genes, including IL-10, and co-signalling pathways, including CTLA4, have been associated with allergic drug reactions, but the effect size is lower than with HLA alleles and most associations have not been replicated. Although TCR specificity seems to be important for CBZ-induced SJS/TEN in South East Asian patients, a distinct repertoire may not play a role in reactions to other drugs. New mass spectrometric techniques allowing for the identification of naturally eluted peptides from drug-exposed HLA alleles will allow for the antigenic source of T-cell activation to be defined and may shed light on the influence of disease. Indeed, preliminary data highlight the propensity of drug-responsive T cells to cross-react with T cells primed to viral antigens. Furthermore, the environment can epigenetically influence regulatory gene expression, suggesting that an individual's family exposure history may alter immune thresholds and tip the balance toward activation.It is likely that predisposition to allergic drug reactions is multifaceted in most cases. This will require the study of large numbers of patients to detect genetic factors that have a lower effect size than HLA alleles. This should be accompanied by detailed clinical phenotyping of patients and the assessment of the immunological phenotype with respect to the presence and type of drug antigen-responsive T cells.