Frequently the internist is confronted with the nonspecific exanthematous eruption. While often a sign of a benign and self-limiting process, an exanthem also might herald the development of a more severe systemic syndrome. Infections, immune-mediated processes, drug reactions, a neoplasm, and familial syndromes with poor prognoses might all manifest initially with an exanthem. A thorough history and complete physical examination should be performed on all patients who present with an exanthem. Characterization of the exanthem morphology, other physical examination findings, and review of systems can help guide laboratory testing and ensure prompt diagnosis and early treatment of potentially life-threatening conditions. This article provides a brief overview of the conditions that must be considered in the evaluation of an ill patient with an exanthem.