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Drug hypersensitivities are common reactions due to immunologic responses. They are of utmost importance because they may generate severe and fatal outcomes. Some drugs may cause Adverse Drug Reactions (ADRs), such as drug hypersensitivity reactions (DHRs), which can occur due to the interaction of intact drugs or their metabolites with Human Leukocyte Antigens (HLAs) and T cell receptors (TCRs). This type develops over a period of 24–72 h after exposure and is classified as type IV of DHRs. Acute generalized exanthematic pustulosis (AGEP), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are types of Severe Cutaneous Adverse Reactions (SCARs). In this review, we aim to discuss the types of ADRs, the mechanisms involved in their development, and the role of immunogenetic factors, such as HLAs in type IV DHRs, single-nucleotide polymorphisms (SNPs), and some epigenetic modifications, e.g., DNA/histone methylation in a variety of genes and their promoters which may predispose subjects to DHRs. In conclusion, development of promising novel in vitro or in vivo diagnostic and prognostic markers is essential for identifying susceptible subjects or providing treatment protocols to work up patients with drug allergies as personalized medicine.