Drug hypersensitivity reactions are a diverse group of reactions mediated by the immune system after exposure to a drug. The Gell and Coombs classification divides immunologic DHRs into 4 major pathophysiologic categories based on immunologic mechanism. Anaphylaxis is a Type I hypersensitivity reaction that requires immediate recognition and treatment. Severe cutaneous adverse reactions (SCARs) are a group of dermatologic diseases that result from a Type IV hypersensitivity process and include drug reaction with eosinophilia and systemic symptom (DRESS) syndrome, Stevens–Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP). Other types of reactions are slow to develop and do not always require rapid treatment. Emergency physicians should have a good understanding of these various types of drug hypersensitivity reactions and how to approach the patient regarding evaluation and treatment.