Osteosarcoma is the most common primary malignancy of bone, typically presenting in the first or second decade of life. Unfortunately, clinical outcomes for osteosarcoma patients have not substantially improved in over 30 years. This stagnation in therapeutic advances is perhaps explained by the genetic, epigenetic, and biological complexities of this rare tumor. In this review we provide a general background on the biology of osteosarcoma and the clinical status quo. We go on to enumerate the genetic and epigenetic defects identified in osteosarcoma. Finally, we discuss ongoing large-scale studies in the field and potential new therapies that are currently under investigation.