Resumen: Osteosarcoma (OS) is characterized by its complex ontology. Nevertheless, an array of molecular tools for the global analysis at the genomic or postgenomic level has brought to light a wealth of data illuminating some of the molecular intricacies of this tumor. Systematic molecular profiling driven by the emergence of novel technological platforms is shaping our understanding of OS. This review gathers all the information into a comprehensive and systematic summary, underlining the contribution of each gene, protein, or signaling pathway to OS tumorigenesis. We place special emphasis on their functional relevance in chemoresistance and metastasis, together with their potential clinical impact. This chapter should inspire researchers to explore new avenues with potential clinical impact.