The PTPN11gene encodes SHP-2, a widely expressed cytoplasmic protein tyrosine phosphatase. SHP-2 is essential for activation of the RAS/MAPK signaling cascade. Most mutations are gain-of-function and result in prolonged ligand-dependent activation of the RAS/MAPK cascade. Germ-line PTPN11 mutations cause Noonan syndrome, a developmental disorder characterized by an increased risk of malignancies. Activating somatic mutations in PTPN11 have been documented in certain hematologic malignancies but they are infrequent in solid tumors. The G503V variant results in increased phosphatase activity compared to the wild-type protein in culture. About 3% of all lung cancers harbor somatic mutations in PTPN11 gene but their prognostic and therapeutic significance remains to be fully elucidated. The utility of SHP2 inhibitors continues to be explored in some preclinical studies.