Cutaneous drug reactions are among the most common types of adverse drug reactions. This article focuses on the recognition and management of severe cutaneous drug eruptions, including the drug-hypersensitivity syndrome, serum sickness-like reaction, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Cutaneous reactions are considered severe when they can result in serious skin damage or involve multiple organs. Some of these reactions can cause significant morbidity or death. Each may be confounded by diagnostic difficulties, confusion in ascertaining causality, and treatment challenges.