Despite aggressive surgical and chemotherapy protocols, survival rates for osteosarcoma patients have not improved over the last 30 years. Therefore, novel therapeutic agents are needed. Receptor tyrosine kinases have emerged as targets for the development of new cancer therapies since their activation leads to enhanced proliferation, survival, and metastasis. In fact, aberrant expression and activation of RTKs have been associated with the progression of many cancers. Studies from our lab using phosphoproteomic screening identified RTKs that are activated and thus may contribute to the signaling within metastatic human osteosarcoma cells. Functional genomic screening using siRNA was performed to distinguish which of the activated RTKs contribute to in vitro phenotypes associated with metastatic potential (motility, invasion, colony formation, and cell growth). The resulting RTK hits were then validated using independent validation experiments. From these results, we identified four RTKs (Axl, EphB2, FGFR2, and Ret) that have not been previously studied in osteosarcoma and provide targets for the development of novel therapeutics.