Drug hypersensitivity reactions (DHRs) are type B adverse drug reactions (ADRs) traditionally defined as unpredictable, dose independent and not related to the drug pharmacology. DHRs, also called drug allergy if the immune system involvement is confirmed, represent around one‐sixth of all ADRs and can cause major clinical problems due to their vague clinical presentation and irregular time course. Understanding the underlying pathophysiology of DHRs is very important for their diagnosis and management. Multiple layers of evidence exist pointing to the involvement of the immune system in DHRs. Recent data have led to a paradigm shift in our understanding of the exact pathophysiology of these reactions. Numerous hypotheses proposing explanation on how a low molecular weight drug molecule can elicit an immune reaction have been proposed. In addition to the classical “hapten” hypothesis, the reactive metabolite hypothesis, the pharmacological interaction with the immune system (p‐i) concept, the danger/injury hypothesis and the altered peptide repertoire hypothesis have been proposed. We here introduce the inflammasome activation hypothesis and the cross‐reactivity hypothesis as additional models explaining the pathophysiology of DHRs. Available data supporting these hypotheses are briefly summarized and discussed. We also introduced the cross‐reactivity model, which may provide a platform to appreciate the potential role played by other factors leading to the activation of the immune system. We believe that although the drug in question could be the trigger of the reaction, the components of the immune system mediating the reaction do not act in isolation but rather are affected by the proinflammatory milieu occurring at the time of the reaction. This review attempts to summarize the available evidence to further illustrate the pathophysiology of DHRs.