Drug rash with eosinophilia and systemic symptoms (DRESS) is a rare, severe adverse drug event that appears with a generalized rash, fevers, and dysfunction of 1 or more organ systems. We describe 2 patients (1 adult and 1 pediatric) seen in the emergency department with DRESS, and review the clinical presentations, potential complications, and management of DRESS. Although rare, it can be associated with significant morbidity, including liver failure and death, and should be considered in the differential diagnosis of patients with diffuse rash and systemic symptoms.