SHP2, a protein-tyrosine phosphatase (PTP), is a key signaling regulator in multiple cell signaling processes including the Ras/MAPK pathway. This has led to SHP2 being identified as a therapeutic target in multiple types of cancers and autoimmune disorders. However, the role that the C-terminal residues play when they interact with other SHP2 domains remains unknown. This study presents data to illustrate that the C-terminal residues interact intramolecularly with other domains to inhibit PTP activity. Additionally, the identification of a specific and potent SHP2 inhibitor has proven difficult because of the high homology and positive nature of the PTP active site. This study presents the data from a high throughput fragment screen identifying several promising HIT compounds that may be further developed into potent and selective SHP2 inhibitors. Furthermore, data supporting the development of a selective SHP2 covalent inhibitor from a nonselective core molecule is presented.