Although most cases of anaphylaxis are treated in the emergency department (ED), personnel may not immediately recognize anaphylaxis based on presenting symptoms because it has a wide range of clinical manifestations and variable progression. When symptoms happen to be atypical or mild and when no trigger is identified, the diagnosis of anaphylaxis can be challenging. Underdiagnosis of anaphylaxis can lead to delayed use of appropriate first-line epinephrine in favor of treatments that should be used as adjunctive only. Even when anaphylaxis is recognized, the choice between an epinephrine autoinjector or epinephrine ampule can still present a challenge. Treatment of anaphylaxis in the ED should include a combination of intramuscular epinephrine, supplemental oxygen, and intravenous fluids. If there is an incomplete response to the initial dose of epinephrine, additional doses or other measures may be considered. The most important management consideration is avoiding treatment delays, because symptoms can progress rapidly. Upon discharge from the ED, all patients with anaphylaxis should be given a prescription for at least 2 epinephrine autoinjectors, an initial emergency action plan, education about avoidance of triggers, and a referral to an allergist. A significant limitation of current studies is that clinical outcomes in anaphylaxis associated with established poor rates of diagnosis and use of recommended treatments are unclear; such trials must be conducted as supporting evidence for ED management guidelines for anaphylaxis.