Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe dermatologic reactions with mucocutaneous involvement that carry elevated mortality rates. They differ along a spectrum of severity based upon body surface area affected. These conditions, usually caused by a drug or infection, are believed to result from cell-mediated and often drug-specific cytotoxic reactions against keratinocytes, leading to widespread dermal-epidermal detachment. Studies attempting to identify potential curative therapies such as intravenous immune globulin (IVIG) and corticosteroids remain inconclusive. However, improved outcomes have been demonstrated by early withdrawal of offending medications, early transfer to an intensive care unit or burn unit, and aggressive supportive care. Due to the rare incidence of SJS and TEN, its recurrence among survivors hints at future vulnerability for these patients, and notorious offending medications should thus be avoided. This clinical review will highlight the diagnostic and therapeutic challenges posed by SJS and TEN, while emphasizing the need to maintain them high on the emergency medicine physician's differential. The review will also detail the supportive measures to take for preventing the rapid progression of mucocutaneous complications and subsequent sepsis-related mortality.