Since the introduction of standardized chemotherapy protocols of osteosarcoma a lot of new aspects in prognosis and curability of these have best developed. Current subclassification which divided osteosarcoma into a conventional type and eleven important recognizable varieties is one of the reason for this success. Cytological grading also serves as a good indicator for the prognosis and is an important criterion for application of adjuvant chemotherapy. Several structure proteins of the extracellular matrix have gained importance in making the diagnosis of an osteosarcoma. Immunohistochemically and biochemically evaluations could show that different collagenous-proteins can be useful for the differential diagnosis of bone tumors. The integration of molecular pathologic methods into the structural morphologic findings will be helpfull in the identification of mutated structure proteins. Oncogenes and tumor suppressor genes are of major importance for the tumorigenesis of osteosarcoma. The prognostic significance of the inactivation of p53 and RBI gene remains to be elucidated. Resistance to chemotherapy is the major mechanism responsible for the failure of osteosarcoma treatment. The main cause for this failure is multidrug resistance, which is often related to a plasma membrane protein, the P-glycoprotein. Immunohistologic investigations of P-glycoprotein are not sufficient to demonstrate the possible association between overexpression of this protein and tumor progression.