A new pathophysiologically based classification of itch is proposed, which should help the clinician adopt a rational approach to diagnosis and management of generalized itch. Focusing on neurogenic itch (itch without visible rash), common causes are reviewed and guidelines for laboratory and radiologic investigation are proposed. A stepwise approach to the management of generalized itch resulting from systemic disease is recommended. Specifically, the relative merits of broad versus narrowband ultraviolet B (UVB) are discussed and the pros and cons of doxepin, opioid antagonists, and selective serotonin reuptake inhibitors (SSRIs) such as paroxetine are considered. Attention is drawn to some novel approaches, including bright-light phototherapy and molecular adsorbent recirculating system (MARS) for selected patients with intractable itch caused by hepatic failure, and mirtazapine for nocturnal itch.