Idiopathic anaphylaxis (IA) is a diagnosis of exclusion that is made when no identifiable causative factors can be found for an episode of anaphylaxis. IA is a potentially life-threatening disease that is the result of a nonimmunologic mast cell activation syndrome. Acute presentation and treatment of these patients is most often in the emergency department and is clinically the same as anaphylaxis from allergens. Since these episodes are unpredictable and often recurrent, these patients are at risk of death if not identified on acute presentation and managed appropriately. As an increasing number of patients are being diagnosed with IA, they will be presenting to emergency departments with initial and recurrent episodes of IA. Therefore, increased awareness of IA and coordinated care is needed so that the morbidity and mortality of this potentially fatal disease can be kept at a minimum.