Osteosarcoma (OS) is one of the most malignant tumors particularly occurring in children, adolescents, and young adults. Over the past few decades, the combined use of chemotherapeutics with aggressive surgery has improved the 5-year survival rates of patients. When the tumor metastasizes to the lung, almost all patients succumb to death. However, approximately 10% to 20% of patients with OS have metastases at the initial diagnosis. Furthermore, conventional chemotherapy is always accompanied with toxic and adverse effects that compromise the quality of life of patients. Therefore, new research and therapeutic methods were proposed by researchers. Current study reviewed differentiation therapy, cancer stem cells and osteogenic differentiation in osteosarcoma