The etiology of osteosarcoma (OS) remains enigmatic. Particular clinical and molecular patterns, observed with high frequency in OS, suggest that it results from some yet-to-be-discovered central driver. How else can biology generate such an aggressive, metastatic, genetically and chromosomally unstable malignancy with virtually no apparent precursor neoplasms that are partway along a disease path toward OS? With this conundrum as a backdrop, the discovery of every new native molecule with power to impact a cell's biology is usually quickly followed by a search to see if this type of molecule contains the key to unlock OS biology.