Post-translational modification by ubiquitin and ubiquitin-like proteins (collectively referred to as UBLs) is a predominant eukaryotic regulatory mechanism. The vast reach of this form of regulation extends to virtually all eukaryotic processes. UBL modifications play critical roles in controlling the cell cycle, transcription, DNA repair, stress responses, signaling, immunity, plant growth, embryogenesis, circadian rhythms, and a plethora of other pathways. UBLs dynamically modulate target protein properties including half-life, subcellular localization, enzymatic activity, conformation, and intermolecular interactions. Moreover, the enzymatic process of UBL ligation to and removal from proteins is itself dynamic, involving cascades of E1, E2, and E3 enzymes antagonized by deubiquitinating enzymes. The UBL C-terminus is first activated, then transferred between multiple enzyme active sites, and ultimately ligated via an E3 enzyme to a target. With roughly 300 members in humans, the largest E3 family consists of the multisubunit Cullin-RING ligases (CRLs), which regulate a staggering number of biochemical pathways and biological processes. The second largest E3 family and first to be identified were the HECT E3s, which regulate such diverse protein functions as protein trafficking, tumor suppression, and transcription. Despite using completely distinct catalytic mechanisms, we have found that the functions of both classes of E3 are modulated through protein-protein interactions influencing enzyme conformation. In my presentation, I will discuss dynamic mechanisms underlying regulation of and by these large families of ubiquitin E3 ligases.