Urticaria is a common skin disorder with a long differential diagnosis. Most cases are readily treated symptomatically and have no systemic implications. However, a number of diseases and syndromes, including vasculitides, immunologic disorders, infectious diseases, hematologic diseases, and autoinflammatory syndromes, can present with urticaria and systemic symptoms, which may lead to hospitalization of the patient. These urticarial syndromes are important to recognize as they often have significant health implications. A comprehensive history and physical exam is important in distinguishing cases of simple urticaria from these syndromes. The presence of atypical wheals, systemic symptoms such as fever or arthralgia, and a lack of response to antihistamine therapy are important diagnostic clues that should prompt further workup.