PURPOSE OF REVIEW: The present article reviews the recent literature on the identification of human leukocyte antigen (HLA) alleles as major susceptible genes for drug hypersensitivity and discusses the clinical implications. RECENT FINDINGS: Several recent studies have reported strong genetic associations between HLA alleles and susceptibility to drug hypersensitivity. The genetic associations can be drug specific, such as HLA-B*1502 being associated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), HLA-B*5701 with abacavir hypersensitivity and HLA-B*5801 with allopurinol-induced severe cutaneous adverse reactions. A genetic association can also be phenotype-specific, as B*1502 is associated solely with carbamazepine-SJS/TEN, and not with either maculopapular eruption or hypersensitivity syndrome. Furthermore, a genetic association can also be ethnicity specific; carbamazepine-SJS/TEN associated with B*1502 is seen in south-east Asians but not in whites, which may be explained by the different allele frequencies. SUMMARY: The strong genetic association suggests a direct involvement of HLA in the pathogenesis of drug hypersensitivity when the HLA molecule presents an antigenic drug for T cell activation. The high sensitivity/specificity of some markers provides a plausible basis for developing tests to identify individuals at risk for drug hypersensitivity. Application of HLA-B*1502 genotyping as a screening tool before prescribing carbamazepine could be a valuable tool in preventing carbamazepine-induced SJS/TEN in south-east Asian countries.