The discovery of new associations between drug toxicities and specific HLA alleles has been facilitated by the use of DNA-based molecular techniques and the introduction of higher-resolution HLA typing, which have replaced serological typing in this field of study. Drug toxicity/HLA associations have been best documented for immunologically mediated reactions, such as drug hypersensitivity reactions associated with the use of abacavir, and severe cutaneous adverse drug reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis induced by carbamazepine and allopurinol use, respectively. The implementation of HLA-B*5701 screening for the prevention of abacavir hypersensitivity syndrome (ABC HSR) has provided a model approach that can be applied to the screening of other drugs. High-level clinical evidence supporting HLA-B*5701 screening for ABC HSR has converged with experimental findings characterizing the CD8+T-cell HLA-B*5701-restricted immune response triggered by abacavir. This has been followed by the successful development of simplified inexpensive and quality-assured laboratory tests for HLA-B*5701 and ongoing quality assurance programs, resulting in a paradigm both for the implementation of HLA-B*5701 screening for HIV providers as well as for the broader successful implementation of pharmacogenetic screening in the clinic.