LocationOsteosarcoma's location with regard to primary tumors is typically unique to intramedullary, metaphyseal regions of Abstract Osteosarcoma is the most common primary malignancy of bone, typically presenting in the first or second decade of life. Osteosarcoma is a very aggressive type of tumor, which has devastating effects on the patient. Especially, pediatric patients suffering from osteosarcoma, are very vulnerable to its side-effects. Most patients suffering from osteosarcoma have a very poor prognosis and thus the understanding of its mechanisms, both oncogenetic as well ontogenetic are of crucial importance. The stagnancy of clinical outcomes may is explained by heterogeneity and complexity as well as genetic background. Not many studies have dealt with the molecular mechanisms of resistance to radiation therapy in osteosarcoma, yet the main genes proposed for their participation include p53, p21, NF-κB, RAS, Rb and GRIM-19. In addition, recent studies have highlighted the role of epigenetic mechanisms in osteosarcoma resistance to therapy and in particular the role of miRNAs. Due to the devastating effect of the disease to the suffering patients, more studies are required in order to unravel the radiation-induced cell death resistance.