Ligand dependent activity of receptor tyrosine kinases is critical for modulating downstream signaling and cell proliferation. In normal cellular context, hepatocyte growth factor (HGF) regulates MET kinase activation and mediates cell proliferation, migration and motility. Recent elucidation of the MET extracellular domain suggests that the Sema domain, which bears structural similarity to other Semaphorins and Plexin family members, plays a critical role in ligand mediated receptor activation. Overexpression of MET which is observed in many cancers leads to ligand independent receptor dimerization and activation. Evidence to support a role for the Sema domain in cancer and therapeutic implications of targeting the Met Sema domain are discussed in this review.