While HACE1 is a well‐known tumor suppressor, its structure and mode of ubiquitination are not understood. The authors present the cryo‐EM structures of human HACE1 along with in vitro functional studies that provide insights into how the enzymatic activity of HACE1 is regulated. HACE1 comprises of an N‐terminal AKR domain, a middle (MID) domain, and a C‐terminal HECT domain. The gene discussed is HACE1; the disease is neoplasm.