Osteosarcoma (OS) is the most frequent bone-forming malignancy in children and adolescents. Concerning its molecular landscape, there is no a direct relationship with a specific gene, but a combination of genetic events. A broad spectrum of activated oncogenes and downregulated suppressor genes has been already explored and considered crucial for its progressive pathogenesis. Mechanisms of gene deregulation include amplifications, point mutations, allelic losses and also epigenetic abnormalities such as aberrant promoter methylation. Although a significant progress in understanding the molecular nature of the OS has been achieved, its aggressive phenotype - characterized by high metastatic potential - remains unexplored. Novel targeted therapeutic strategies include monoclonal antibodies (mABs) and also tyrosine-kinase inhibitors (TKIs). Additionally, sophisticated and innovative diagnostic techniques, such as 18 fluorodeoxyglucose positron emission tomography plus CT (18F-FDG/PET/CT), provide critical data regarding its biological behavior. In the current paper, we present novel molecular and metabolic advances by analyzing OS genetic profile and biochemical microenvironment.