Protein tyrosine phosphatase plays an important role in maintaining protein tyrosine phosphoryla-tion homeostasis. SHP2 is the first confirmed carcinogenic protein tyrosine phosphatase, whose dysregulation is closely related to the occurrence and development of a variety of malignant tu-mors. As the intersection of multiple signaling pathways, SHP2 not only affects the proliferation, metastasis and invasion of tumor cells, but also participates in PD-1/PD-L1-mediated tumor im-mune escape, promoting the occurrence and development of tumors in many aspects. Therefore, SHP2 has been considered as an ideal target for cancer intervention. However, over the years, ef-forts to develop anti-tumor drugs targeting SHP2 have had little success. Hence, SHP2 was once con-sidered as an “undruggable” target. It is only recently that the clinical development of allosteric SHP2 inhibitors, represented by TNO155, has brought hope for tackling this challenging target. So far, there have been 13 candidates in clinical trials. This review briefly introduces the structure and functions of SHP2 and its correlation with tumors, and focuses on the development process and clinical trial progress of allosteric SHP2 inhibitors in recent years.