Pruritus is the most common symptom of skin disease. Even in the absence of primary cutaneous findings, severe and extensive pruritus often is associated with systemic disease. This review considers briefly the physiology of pruritus and discusses the various systemic diseases often accompanied by this bothersome symptom. In addition to exploring the possible mechanisms and potential therapies of itching in selected disorders, this review presents general recommendations for evaluating patients with unexplained pruritus and management guidelines for alleviating their discomfort.