Maintenance of cellular function requires timely and selective degradation of key regulatory proteins. For example, progression of the mammalian cell cycle is regulated by phosphorylation/dephosphorylation and synthesis/degradation of many key proteins via the ubiquitin pathway. Ubiquitin, a soluble protein of 76 amino acids, is enzymatically attached to an ε-NH2-Lys in a target protein. Ubiquitin-conjugated proteins are recognized and degraded by the 26S proteasome. Ubiquitination requires ubiquitin-activating enzyme E1, ubiquitin-conjugating enzymes E2, and ubiquitin ligases E3. The direction of ubiquitin transfer is from E1 to E2 and from E2 to E3. Itch, a novel E3 ubiquitin ligase, is absent in the Non-agouti-lethal 18H mice. These mice develop immunological, inflammatory, epithelial, and hematopoietic diseases. Itch contains four WW protein interaction domains, which bind to proline-rich sequences in a fashion similar to SH3 domains. In addition, Itch contains a C-terminal Hect domain, which is conserved in the E3 family of ubiquitin ligases. Thus, Itch is important in the ubiquitin-dependent protein degradation occurring in normal hematopoiesis and inflammation.