Cutaneous adverse drug reactions are unpredictable and include various different skin conditions of varying degrees of severity. The most concerning are usually referred to as severe cutaneous adverse reactions (SCARs) and include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DiHS) or hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). All are delayed type IV hypersensitivity reactions in which a T-cell-mediated drug-specific immune response is responsible for causing the disease. Nonetheless, specific T-cell subpopulations develop in response to certain environmental conditions and produce cytokines that orchestrate the various phenotypes. Cytotoxic T lymphocytes (CTLs), T-helper type 1 (Th1), Th2, Th17, and regulatory T cells (Treg), among other T-cell subpopulations, participate in the development of SCAR phenotypes. Cell subpopulations belonging to the innate immune system, comprising natural killer cells, innate lymphoid cells, monocytes, macrophages and dendritic cells, can also participate in shaping specific immune responses in various clinical conditions. Additionally, tissue-resident cells, including keratinocytes, can contribute to epidermal damage by secreting chemokines that attract pro-inflammatory immunocytes. The final phenotypes in each clinical entity result from the complex interactions between a variety of cell lineages, their products, soluble mediators and genetic and environmental factors. Although the pathophysiology of these reactions is not fully understood, intensive research in recent years has led to major progress in our understanding of the contribution of certain cell types and soluble mediators to the variability of SCAR phenotypes.