Many pruritic conditions do not originate in the skin, but are the result of systemic abnormality. Among the diseases that can cause pruritus are renal insufficiency, cholestasis, Hodgkin's lymphoma, polycythemia vera, solid tumors, and many others. Other pruritic conditions appear to be iatrogenic; opioid-induced pruritus may be the most important in palliative medicine. Successful treatment of the underlying condition usually relieves itch. But, with time, many diseases progress and treatment of the cause will be impossible. Topical treatments may be of limited value. Strategies involving systemic treatments include use of antidepressants, oral opioid antagonists, or cholestyramine. There is no one cure for all pruritic symptoms. Better understanding of mechanisms of pruritus may help develop better treatments.