Despite significant advances in the diagnosis and treatment of osteosarcoma in recent years, overall survival has remained low for over 2 decades. The standard diagnosis of osteosarcoma requires a combination of clinical presentation, radiologic studies, and pathologic tissue evaluation. A typical Codman's triangle in radiologic evaluation is vital in making correct diagnosis for middle or late stage of osteosarcoma. However, there is an actual demand for novel molecular markers with high sensitivity and stability for the diagnosis of early events of osteosarcoma and also the probability of recurrence and metastasis. Except that, some highly relevant gene mutations with these events could also provide valuable information regarding osteosarcoma protection. In this review, we will focus on the molecular markers which have been discovered in recent years with potential application of early stage and recurrence diagnosis and protection.