Resumen: Osteosarcoma (OS) is characterized by its complex ontology. Nevertheless, an array of molecular tools for the global analysis at the genomic or post-genomic level has exposed a wealth of data illuminating some of the molecular intricacies of this tumor. A 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 tumorigenesis of OS. We give special emphasis to their functional relevance to chemoresistance and metastasis, together with their potential clinical impact. This chapter hopefully will provide inspiration to explore new avenues with future clinical impact.