Osteosarcoma (OS) is the most common primary bone tumor in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory. We explored phospho‐ERK 1/2, MCL‐1, phospho‐Ezrin/Radixin/Moesin (P‐ERM) as potential therapeutic targets. The activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS. While, BRAF gene was found mutated in 4/30 OS samples from patients. Based on these results we tested the multikinases inhibitor sorafenib (BAY 43‐9006) in preclinical models of OS. Sorafenib inhibited OS cell lines proliferation, induced apoptosis and downregulated P‐ERK1/2, MCL‐1, P‐ERM in a dose dependent manner. ERM dephosphorylation is not due to ERK inhibition. The downregulation of MCL‐1 increased apoptosis in OS cell lines. In chick embryo chorioallantoic membrane the angiogenesis induced by OS supernatants was blocked by sorafenib treatments. Indeed, sorafenib reduced VEGF and MMP2 production. Sorafenib treatment dramatically reduced tumor volume of OS xenografts and lung metastasis in SCID mice. In conclusion, ERK1/2, MCL‐1 and ERM pathways are active in OS. Sorafenib is able to interrupt their routes in vitro and in vivo displaying antitumoral activity, antiangiogenic effect and reducing metastasis colonies formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients failing standard treatments. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C213.