The ubiquitylation of proteins is carried out by E1, E2 and E3 (ubiquitin ligase) enzymes, and targets them for degradation or for other cellular fates. The HECT enzymes, including Nedd4 family members, are a major group of E3 enzymes that dictate the specificity of ubiquitylation. In addition to ubiquitylating proteins for degradation by the 26S proteasome, HECT E3 enzymes regulate the trafficking of many receptors, channels, transporters and viral proteins. The physiological functions of the yeast HECT E3 ligase Rsp5 are the best known, but the functions of HECT E3 enyzmes in metazoans are now becoming clearer from in vivo studies.