The most aggressive and deadliest form of cancer for adolescence and young adults is osteosarcoma. Current treatment of osteosarcoma mainly consists of chemotherapy along with surgery has dramatically improved survival rate. However unfortunately, the survival-rate remained unchanged in its metastatic stages that might be due to chemoresistance against the treatment of osteosarcoma. Till date, in clinical applications, there is no precise diagnostic/prognostic marker of osteosarcoma. Metallothioneins are thiol rich intracellular proteins, which binds to several cytotoxic agents. Metallothionein isoforms participate actively in numerous physiological and patho-physiological processes like proliferation, apoptosis, angiogenesis, and the heavy metals detoxification. There are many evidences in literature which are suggestive of participation of these proteins in carcinogenesis and antitumor therapy. Furthermore, a number of studies also reveal the important role of metallothioneins in tumor cell defense mechanism against the radiotherapy by preventing apoptosis. Also in osteosarcoma patients in comparison to healthy controls, the higher level of metallothioneins levels further indicates their significant role. Moreover higher level of metallothionein-2A in chemotherapy resistance patients with osteosarcoma further becomes potential supportive evidence. According to the information available in the literature, one may accomplish that metallothioneins has a role in osteosarcoma progression and chemoresistance and may become a potential diagnostic marker as well as a reliable therapeutic target. However, further multicentric studies are needed in support. A better knowledge of the communication among metallothioneins in osteosarcoma as well as with chemotherapeutic agents is necessity and may exposed new perspectives in cancer treatment.