The expression of the ubiquitin related protein Nedd8/RUB is essential for growth in most organisms. Nedd8/RUB has been shown to modify the cullin subunit of culling-based ubiquitin protein ligases (E3). Neddylation acts to regulate the function of these E3s and organisms with lesions in the neddylation process exhibit severe growth defects. In this review we describe the proteins that participate in neddylation and discuss a model for Nedd8/RUB regulation of ubiquitin ligase function.