HECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors, including Mcl1, p53, DDIT4, and Myc. Although mutations in HUWE1 and related HECT ligases are widely implicated in human disease, our molecular understanding remains limited. Here we present a comprehensive investigation of full-length HUWE1, deepening our understanding of this class of enzymes. The N-terminal ∼3,900 amino acids of HUWE1 are indispensable for proper ligase function, and our cryo-EM structures of HUWE1 offer a complete molecular picture of this large HECT ubiquitin ligase. HUWE1 forms an alpha solenoid-shaped assembly with a central pore decorated with protein interaction modules. Structures of HUWE1 variants linked to neurodevelopmental disorders as well as of HUWE1 bound to a model substrate link the functions of this essential enzyme to its three-dimensional organization. Display omitted •Structure of a full-length HECT ligase reveals modular assembly•HUWE1 folds into ring-shaped architecture with flexibly attached accessory domains•Patient mutations interfere with HUWE1 ligase activity•Armadillo repeats in the ring architecture contribute to substrate binding Hunkeler et al. present the cryo-EM structure of HUWE1, a large HECT E3 ligase that forms a modular ring-shaped assembly with flexibly attached accessory domains. The influence of mutations associated with intellectual disabilities on HUWE1 activity and substrate recognition by HUWE1 is dissected biochemically and structurally.