Osteosarcoma cells derived from patients have been isolated and subsequently cultured for the past 35 years. To date though, there have been no major breakthroughs in the development of a model for osteosarcoma that uses orthotopic implantation of human osteosarcoma cells and that closely emulates the clinical progression of this debilitating and fatal disease. Such a model is long overdue given the devastating demographics (second highest cause of cancer-related death in the paediatric age group) of the ailment and the lack of solid options for control, if not cure, for the disease, as it also is the most common primary tumour of bone. Only then can more robust R & D be undertaken in the search for efficacious anti-osteosarcoma agents. This review tackles this conundrum and lists the variety of models (that use human osteosarcoma cells) available and the types of studies performed with these.