The primary malignant bone tumor, osteosarcoma, is a deadly disorder. Its etiology is complex, and treatment is mostly obscure. The transcription factors (TFs) involved in epithelial to mesenchymal transition (EMT) have significant role in osteosarcoma. A number of evidence suggests that overexpression of EMT-TFs, such as Twist, Snails and Zebs, is involved in complex pathogenesis of osteosarcoma. Recent research studies have showed some extent of promise in osteosarcoma treatment by targeting these EMT-TFs. However, success in research on osteosarcoma-EMT-TFs axis is just in primary stage, and a long way to go. Targeting Twist, Snail or Zeb by specific molecules or chemotherapeutic agents may provide a new dimension in osteosarcoma treatment by controlling metastasis.