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Ubiquitin ligases (E3 enzymes) transfer ubiquitin from ubiquitin-conjugating (E2) enzymes to target proteins. By determining the selection of target proteins, modification sites on those target proteins, and the types of ubiquitin modifications that are formed, E3 enzymes are key specificity factors in ubiquitin signaling. Here, I summarize our knowledge of the structural mechanisms in the HECT E3 subfamily, many members of which play important roles in human disease. I discuss interactions of the conserved HECT domain with E2 enzymes, ubiquitin and target proteins, as well as macromolecular interactions with regulatory functions. While we understand individual steps in the catalytic cycle of HECT E3 enzymes on a structural level, this review also highlights key aspects that have yet to be elucidated. For instance, it remains unclear how diverse target proteins are presented to the catalytic center and how certain HECT E3 enzymes achieve specificity in ubiquitin linkage formation. The structural and functional properties of the N-terminal regions of HECT E3 enzymes that likely act as signaling hubs are also largely unknown. Structural insights into these aspects may open up routes for a therapeutic intervention with specific HECT E3 functions in distinct pathophysiological settings.