Definition of the relationship between drug protein adduct formation (haptenation) and development of immunological adverse drug reactions (drug hypersensitivity) has been an area of active research for over 80 years. The hapten hypothesis which states that “immunogenicity of low molecular weight organic chemicals is dependent on modification of self-proteins,” evolved from Landsteiner and Jacob’s discovery of a correlation between the reactivity of dinitro-halogenated benzenes and their sensitization potential. The hypothesis rapidly evolved to encompass drugs that often require metabolic activation to generate electrophilic, protein-reactive intermediates. As tissue culture methods advanced, the importance of drug hapten-specific T-cells in the disease pathogenesis was defined. This led to a plethora of studies describing the uptake and processing of drug(metabolite) protein adducts by antigen presenting cells, and the subsequent surface display of hapten-modified peptides in the context of MHC molecules. Although the pathway of hapten-specific T-cell activation is now well established, several questions need to be addressed: first, what is the nature of the hapten-modified peptides displayed by MHC? Second, how many of these peptides stimulate T-cells?; third, what are the critical protein modifications involved in T-cell activation; and finally, what is the role of hapten-specific T-cells in the iatrogenic disease? These questions will become increasingly important as more and more targeted covalent binding inhibitor drugs are approved for human use. In this review, we provide a brief synopsis of hapten research and then describe the approaches used by Pharma and academia to study hapten covalent binding and the role of drug protein adducts in the activation of human T-cells.