Various membrane-bound proteins are proteolytically cleaved to release their extracellular domain. This proteolytic mechanism, also called ectodomain shedding, may appear inconsiderable, with no significant physiological role. It is therefore not surprising that this phenomenon has been overlooked in the past and has been considered a mere degradation process of membrane-bound proteins. However, as I discuss in this review, studies during the past two decades have revealed that ectodomain shedding is an essential post-translational mechanism with critical roles during development, in homeostasis, and under pathological conditions in vivo. 1–3 As its name suggests, tumor necrosis factor α (TNFα)-converting enzyme (TACE), also known as a disintegrin and metalloprotease 17 (ADAM17), was originally identified as an enzyme responsible for releasing the membrane-bound TNFα precursor to produce biologically active soluble TNFα. 4, 5 However, studies over the past decade have identified a wide range of membrane-bound proteins in addition to TNFα as substrates for TACE, 1–3 including the ligands for epidermal growth factor receptor (EGFR), 6 which are also produced as membranebound precursors and are cleaved to become fully functional. TACE is, therefore, an essential modulator of the TNFα–TNFα receptor signaling pathway and the EGFR ligand–EGFR signaling pathway in vivo. 7 Because TNFα and EGFR are involved in the pathogenesis of many disorders, such as rheumatoid arthritis and breast cancer, respectively, TACE has now emerged as a potential molecular target for treating these conditions. 8, 9 In this review, I will outline the history of TACE, beginning with its identification, and summarize some of the recent findings uncovered using TACE mutant mice.