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Notch signaling plays an important role in developmental processes and adult tissue homeostasis. Altered Notch signaling has been associated with various diseases including cancer. While the importance of altered Notch signaling in cancers of hematopoietic and epithelial origins has been established, its role in tumors of mesenchymal origin is less clear. Here, we report that human osteosarcoma cell lines and primary human osteosarcoma tumor samples show significant up-regulation of Notch, its target genes and Osterix. Notch inhibition by γ-secretase inhibitors or by using lentiviral mediated expression of dominant negative Mastermind-like protein (DN-MAML) decreases osteosarcoma cell proliferation in vitro. In vivo, established human tumor xenografts in nude mice show decreased tumor growth after chemical or genetic inhibition of Notch signaling. Finally, transcriptional profiling of osteosarcomas from p53 mutant mice confirmed up-regulation of Notch1 target genes Hes1, Hey1 and its ligand Dll4. Our data suggest that activation of Notch signaling contributes to the pathogenesis of human osteosarcomas and its inhibition may be a therapeutic approach for the treatment of this mesenchymal tumor.