The appropriate management of the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is paramount because it is associated with significant morbidity and mortality. This syndrome shares clinical features with other dermatologic conditions, including other severe cutaneous drug reactions, requiring the clinician to carefully examine the proposed criteria to make the appropriate diagnosis. Once the diagnosis of DRESS syndrome has been established, the next step in management is immediate cessation of the causative medication(s). In cases in which the culprit drug is not obvious, clinicians must use their clinical judgment to select which medication to discontinue. They may also utilize patch or lymphocyte transformation tests to aid in identification when appropriate. Topical corticosteroids can be used for symptomatic relief, but systemic steroid therapy is generally required. Other immunosuppressants have also been employed in treatment and show promise in future therapy. Patients with DRESS syndrome should be managed in an intensive care or burn unit for appropriate care and infection control. In addition, appropriate specialists should be consulted based on the affected organ systems. Most patients recover completely after drug withdrawal and appropriate therapy. However, some patients with DRESS syndrome suffer from chronic complications and approximately 10% die, primarily from visceral organ compromise. Controlled clinical trials investigating the most appropriate therapies and their risks, particularly intravenous corticosteroids, are lacking, and would be invaluable in determining the optimal future treatment regimen for DRESS syndrome.