Traditional prognostic determinants in osteosarcoma have included demographics (age, sex), tumour size, site, stage, and the response to chemotherapy. Many of these are determined using varying techniques and units of measurement, which can make comparison between studies difficult. The absence of survival difference between limb sparing surgery and amputation has been repeatedly demonstrated in primary disease, and even in the setting of pathological fracture. On the other hand, there is still some controversy over the existence of increased local recurrence for limb-sparing surgery, and the implications of this. Commonly used prognostic determinants such as metastases, and response to chemotherapy enable a high degree of prognostic accuracy but usually at a late stage in the course of disease. Leading on from this, there is a need to uncover molecular pathways with specific influence over osteosarcoma progression to facilitate earlier treatment changes. Some important pathways are already being defined, for example the association of CXCR4 with metastases on presentation, the likelihood of doxorubicin resistance with positive P-glycoprotein, and the reduced survival prediction of over expressed survivin. It is anticipated that the future of osteosarcoma treatment will involve treatment tailored to the molecular profile of tumours at diagnosis, adjuvant therapy directed towards dysfunctional molecular pathways rather than the use of cytotoxics, and a more standardised approach to the measurement of clinical prognostic factors.