Human HB-EGF was initially identified as a protein of 22 kD secreted by macrophage-like U937 cells. It belongs to the EGF family of proteins that includes EGF, TGF-α, heparin-binding EGF like-growth factor (HB-EGF), epigen, epiregulin, betacellulin, neuroregulin, and tomoregulin. All the EGF family members are synthesized as type I membrane protein precursors, which can undergo proteolytic cleavage at the plasma membrane to release a mature soluble ectodomain.? It has been suggested that various metalloproteinases participate in the shedding of HB-EGF, such as MMP-3, MMP-7, ADAM9, ADAM10, ADAM12, and ADAM17. The ectodomain shedding is stimulated by phorbol esters, calcium ionophore, lysophosphatidic acid, and IL-1β. In addition, nardilysin, a metalloendopeptidase of the M16 family, binds HB-EGF and enhances its shedding through activation of TACE (ADAM17). The membrane-anchored HB-EGF acts in cell-cell and cell-extracellular matrix interactions; in addition, the membrane HB-EGF is the receptor for diphtheria toxin that can be internalized and induce apoptotic death. HB-EGF plays a crucial role in cardiac valvulogenesis; newborn knockout mice have malformed semilunar and atrioventricular heart valves and poorly differentiated lungs. HB-EGF is overexpressed in several types of cancer such as pancreatic carcinoma, ovarian cancer, and gastric carcinoma. Also, HB-EGF is involved in cancer metastasis and invasion of ovarian cancer, head and neck cancer, and thyroid carcinoma cells.