TGF-α was initially identified in the culture medium of several transformed cell lines. TGF-α is structurally and functionally related to the epidermal growth factor and belongs to the EGF subfamily that also includes amphiregulin (AR), heparin binding EGF-like growth factor (HB-EGF), betacellulin (BTC), epiregulin (EPR), and epigen (EPG). TGF-α is derived from a transmembrane precursor (20-22 kD); pro-TGFα undergoes several posttranslational modifications that include N- and O-linked glycosylation and palmitoylation. The pro-TGFα includes a glycosylated N-terminal domain, a TGF-α region with the EGF-like motif, a linker sequence that joins the ectodomain to the transmembrane domain, and an intracellular portion. TGF-α is proteolytically released from the membrane by tumor necrosis factor-α converting enzyme (TACE/ADAM-17). TGF-α is cleaved at the N- and C-terminus of the EGF motif; the proteolytic cleavage at the C-terminus is required to release the soluble form. The N-terminal cleavage of pro-TGFα occurs at the cell surface by TACE-independent activity. TGF-α plays a key role regulating follicle development and tumorigenesis. TGF-α and its receptor are highly expressed in papillary thyroid carcinoma. Also, TGF-α polymorphism has been associated with oral birth defects.