Abstract: EGF family growth factors, including transforming growth factor‐alpha (TGFα), amphiregulin (AR), and heparin‐binding EGF (HB‐EGF), are invariably expressed as transmembrane precursors that are cleaved at one or more sites in the extracellular domain to release soluble growth factor. Considerable attention has focused on the identification of proteases responsible for these processing events. We previously implicated tumor necrosis factor‐alpha converting enzyme (TACE/ADAM17) in the generation of soluble TGFα from its transmembrane precursor, proTGFα. Here, we review our findings that primary keratinocytes from Tace^ΔZn/ΔZn mice, which express a nonfunctional TACE, released dramatically lower levels of soluble TGFα compared to their normal counterparts, even though TGFα mRNA and cell‐associated protein levels were similar in the two cell populations. Restoration of TACE activity in Tace^ΔZn/ΔZn cells increased shedding of TGFα species, including the mature, 6‐kDa protein. Further, exogenous TACE enzyme accurately cleaved the N‐terminal processing site of proTGFα in cell lysates, as well as both physiologic sites of a soluble proTGFα ectodomain. TACE also accurately cleaved peptide substrates corresponding to the processing sites of several additional EGF family members, and restoration of TACE activity enhanced the shedding of soluble AR and HB‐EGF proteins from Tace^ΔZn/ΔZn cells. Finally, reduction of functional TACE gene dosage greatly exacerbated the open‐eye defect of Egfr^{wa‐2/wa‐2} newborns, which is regulated by redundant actions of several EGF family ligands. The implications of these results for the biology of the EGF family and TACE are discussed.