Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. Existing treatment options and surgical intervention are unable to effectively manage this tumor. Therefore, novel mechanism-based targets and strategies need to be rationally established to strive for improvement in the survival of patients diagnosed with osteosarcoma. The serine/threonine kinases Polo-like kinase (Plk) 1 is a key regulator of cell division in eukaryotic cells. Plk1 gene and protein expression has been proposed as a new prognostic marker for many types of malignancies, and Plk1 is a potential target for cancer therapy. In this review, we shall discuss the studies which indicate that Plk1 could be an excellent target for the treatment of osteosarcoma.