The human leukocyte antigen (HLA) molecules encoded within the human major histocompatibility complex are a group of highly conserved cell surface proteins, which are related to antigen recognition. HLA genes display a high degree of genetic polymorphism, which is the basis of individual differences in immunity. Specific HLA genotypes have been highly associated with typical adverse drug reactions. HLA-A31:01 and HLA-B15:02 are associated with carbamazepine-induced severe cutaneous adverse reactions, HLA-B57:01 is related to abacavir-induced drug-induced hypersensitivity syndrome and flucloxacillin/pazopanib-induced drug-induced liver injury, while HLA-B35:01 is a potential biomarker for predicting polygonum multiflorum-induced liver injury. It is not clear how small drug molecules to interact with HLA molecules and T cell receptors (TCR). There are four mechanistic hypotheses, including the hapten/prohapten theory, the pharmacological interaction concept, the altered peptide repertoire model, and the altered TCR repertoire model.