Tyrosyl phosphorylation participates in various pathological and physiological processes, which are regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). The Src homology-2 domain containing phosphatase SHP2 (encoded by PTPN11) is an important phosphatase, which was found to be implicated in the regulation of genetic disease, development, metabolic, neurological, muscle, skeletal disease and cancer. Germline mutations in PTPN11 cause the Noonan Syndrome, LEOPARD syndrome and metachondromatosis. Somatic PTPN11 mutations occur in hematologic malignancies and in solid tumors. SHP2 is also an important component in oncogenic signaling pathways. It may play different roles in different stages and positions of human cancers. Whether SHP2 is an oncogene or cancer suppressor gene remains to be elucidated. Elucidation of the regulatory mechanisms of SHP2 in human disease will provide new insights into disease and new targets for therapy. Here, we summarized the structural basis and recent research progression on SHP2 in various human disease, including genetic and cancer diseases.