Neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) is the prototypical protein in a family of E3 ubiquitin ligases that have a common domain architecture. They are comprised of a catalytic C-terminal HECT domain and N-terminal C2 domain and WW domains responsible for cellular localization and substrate recognition. These proteins are found throughout eukaryotes and regulate diverse biological processes through the targeted degradation of proteins that generally have a PPxY motif for WW domain recognition, and are found in the nucleus and at the plasma membrane. Whereas the yeast Saccharomyces cerevisiae uses a single protein, Rsp5p, to carry out these functions, evolution has provided higher eukaryotes with several related Nedd4 proteins that appear to have specialized roles. In this review we discuss how knowledge of individual domain function has provided insight into the physiological roles of the Nedd4 proteins and describe recent results that suggest discrete functions for individual family members.