Despite the knowledge of many of the genetic alterations present in osteosarcoma, its complexity precludes placing its biology into a simple conceptual framework. In contrast to many other malignancies, multiple genetic and environmental factors can all lead to the development of osteosarcoma which is defined phenotypically rather than molecularly. Despite the many factors capable of leading to its development, osteosarcoma is a rare malignancy that is relatively homogeneous in its clinical behavior and chemotherapy response. It remains unknown whether the clinical features of osteosarcoma are defined by the cell of origin, the genetic events leading to transformation, the timing of those events or factors related to differentiation into an osteoblastic phenotype. Identifying new treatment approaches has generally been through empiric and screening approaches. In this presentation the genetic alterations present in osteosarcoma, issues related to the cell of origin and bone differentiation will be reviewed along with the recent results of preclinical drug screening.