Adverse drug reactions (ADRs) cost the Australian health care system over $660 million annually and complicate the use and public trust of key pharmaceuticals.  In recent years numerous associations between immune mediated ADRs and specific Human Leukocyte Antigen (HLA) alleles have been identified.  These molecules are cell surface glycoproteins responsible for the presentation of peptides, derived from the breakdown of both endogenous and exogenous proteins, at the cell surface for immune surveillance.  In health, constitutive HLA-peptide complexes are inert, whilst HLA molecules in complex with novel or foreign peptides (e.g. those derived from invading pathogens) may stimulate a T cell response.  We recently defined the mode of interaction of the anti-retroviral drug abacavir with HLA-B*57:01, the allele associated with the potentially lethal ADR, abacavir hypersensitivity syndrome. Using a combination of mass spectrometry and structural biology, we showed that abacavir bound within the peptide-binding groove of HLA-B*57:01 altering the selection of self-peptides, causing significant perturbation of the immunopeptidome (the peptides displayed by the HLA), and presenting T cells with countless novel, immunogenic, HLA-B*57:01-abacavir-self-peptide complexes¹.  Here, we extend these studies to other ADRs and use mass spectrometry (targeted and data dependent acquisition methods) and T cell activation assays to monitor drug induced changes in the immunopeptidome and the immunogenicity of ADR associated HLA molecules.  Recent data on the application of these techniques to investigate interactions between allopurinol (and its metabolites) and HLA-B*58:01, implicated in allopurinol hypersensitivities such as the severe cutaneous reactions Stevens-Johnson syndrome and Toxic Epidermal Necrolysis, will be discussed.