The protein tyrosine phosphatase SHP2 encoded by PTPN11 is a promising therapeutic target for cancer therapy, while the multifaceted roles of SHP2 complicate the drug discovery targeting SHP2. Given the biological significance of SHP2, strategies targeting SHP2 have been developed in recent years. To date, eight SHP2 inhibitors have advanced into clinical trials as mono- or combined therapy for treating solid tumors or adaptive resistant cancers. In this Perspective, we briefly summarize the strategies targeting SHP2 including inhibitors, activators, and proteolysis-targeting chimera (PROTAC) degraders. Besides, targeting the protein-protein interactions between SHP2 and other adaptor proteins is also discussed. Finally, we also highlight the target- and pathway-dependent combination strategies of SHP2 for cancer therapy. This Perspective may provide a timely and updated overview on the strategies targeting SHP2 for cancer therapy.