Mouse betacellulin was identified in the conditioned medium of mouse pancreatic beta cell tumors. 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 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. ADAM10 seems to be the main releasing enzyme for betacellulin and EGF. Human betacellulin precursor protein exhibits 79% similarity with the mouse precursor at the amino acid level. The expression of betacellulin mRNA is high in the pancreas, liver, kidney, and small intestine. Betacellulin induces the proliferation of endocrine precursor cells in the pancreas, a fetal pancreatic epithelial cell line, and a rat insulinoma cell line. In addition, betacellulin induces proliferation and regeneration of pancreatic beta cells in diabetic mice, a process that is linked to the transcription of homeobox-1 and insulin receptor substrate (IRS)-2. These genes are involved in beta cell proliferation. Betacellulin binds not only to the EGFR, it also binds and activates all possible heterodimeric combinations of the related ErbB receptors including the highly oncogenic ErbB2/3 dimer and homodimers of ErbB4. Betacellulin is expressed in lung cancer cells, hepatocellular carcinoma, and head-and-neck squamous carcinoma cells among others, and it is associated with tumor growth progression, angiogenesis, and invasiveness.