Non-agouti-lethal 18H (a^18H) mice are dark agouti with black pinna hairs. What makes these mice unique is that they develop a spectrum of immunological diseases not seen in other agouti mutant mice1. On the JU/Ct background, a^18H mice develop an inflammatory disease of the large intestine. On the C57BL/6J background, they develop a fatal disease characterized by pulmonary chronic interstitial inflammation and alveolar proteinosis, inflammation of the glandular stomach and skin resulting in scarring due to constant itching, and hyperpla-sia of lymphoid cells, haematopoietic cells and the forestomach epithelium. Previous studies suggested that the a^18H mutation results from a paracentric inversion that affects two loci: agouti and another, as yet unidentified locus designated itchy (the provisional gene symbol is Itch), that is responsible for the immunological phenotype of a^18H mice¹. Here we confirm that a^18H results from an inversion and show that Itch encodes a novel E3 ubiquitin protein ligase, a protein involved in ubiqui-tin-mediated protein degradation. Our results indicate that ubiquitin-dependent proteolysis is an important mediator of the immune response in vivo and provide evidence for Itch's role in inflammation and the regulation of epithelial and haematopoietic cell growth.