c-MET is a disulfide-linked α/β heterodimeric cell surface tyrosine kinase receptor. Hepatocyte growth factor (HGF; also known as scatter factor) is the only known c-MET ligand. Binding of HGF to c-MET triggers c-MET receptor activation via autophosphorylation of the cytoplasmic domain and recruitment of adaptor proteins that potentiates cell signaling. Aberrant HGF/c-MET signaling via ligand dependent (both paracrine and autocrine) and ligand independent mechanisms is well documented in several human cancers and multiple therapeutic agents targeting this pathway are in clinical development. c-MET phosphorylation has been reported in Non-Small Cell Lung (NSCLC) carcinoma, Head and Neck Squamous Cell Carcinoma (HNSCC), and other carcinomas. Like most receptor kinases, improved methods for reliable measurement of c-MET receptor activation are needed.