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Osteosarcomas are genetically complex tumours for which the cell of origin and the molecular pathogenesis are still poorly understood. Despite intensive multimodal treatment protocols only two thirds of patients currently survive the disease which is at least partly due to the early occurring chromosomal instability resulting in marked inter- and intratumoral heterogeneity. This review article outlines the current state of osteosarcoma research with a particular focus on exome- and genome-wide sequencing analyses and potential impacts on new therapeutic opportunities.