The protein tyrosine phosphatase SHP2, encoded by PTPN11, functions as a critical signal transduction regulator and interacts with key signaling molecules in both RAS/ERK and PD-1/PD-L1/ BTLA (B- and T-lymphocyte attenuator) pathways. Targeting SHP2 pharmacologically, therefore, may be a promising therapeutic strategy for many RAS-driven cancers. Multiple small molecule inhibitors of SHP2 (SHP2i) are currently in clinical development, both alone and in combinations. SHP2i combination therapies, including those with inhibitors of EGFR, KRASG12C, BRAFV600E, MEK, ERK, CDK4/6 and PD-1, and other combinations not yet explored, represent targeted strategies with great promise for advanced or refractory RAS-dependent solid tumor malignancies. One recent study demonstrates that combined pharmacologic inhibition of SHP2 and MEK is active in models of NF1-deficient malignant peripheral nerve sheath tumors (MPNST). This article, based on the discovery that a wide range of receptor tyrosine kinases (RTK) are upregulated through the adaptive response to MEKi in this RAS-dysregulated tumor type, adds to the growing body of literature in which SHP2 inhibitors have been combined with other targeted therapies in a range of cancer types. To date, most of these reports have focused on signaling and direct cancer cell related effects of these small molecules. Here, we discuss recent advances in the preclinical and clinical development of SHP2 inhibitors, as well as their potential role in immune signaling modulation as a promising cancer-directed strategy.