Osteosarcoma, the most common malignant bone tumor of childhood, is a high-grade 
primary bone sarcoma that occurs mostly in adolescence. Standard treatment 
consists of surgery in combination with multi-agent chemotherapy regimens. The 
development and approval of imatinib for Philadelphia chromosome-positive acute 
lymphoblastic leukemia in children and the fully human monoclonal antibody, 
anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have 
established the precedent for use of targeted inhibitors along with standard 
chemotherapy backbones. However, few targeted agents tested have achieved 
traditional clinical endpoints for osteosarcoma. Many biological agents 
demonstrating anti-tumor responses in preclinical and early-phase clinical 
testing have failed to reach response thresholds to justify randomized trials 
with large numbers of patients. The development of targeted therapies for 
pediatric cancer remains a significant challenge. To aid in the prioritization 
of new agents for clinical testing, the Pediatric Preclinical Testing Program 
(PPTP) has developed reliable and robust preclinical pediatric cancer models to 
rapidly screen agents for activity in multiple childhood cancers and establish 
pharmacological parameters and effective drug concentrations for clinical 
trials. In this article, we examine a range of standard and novel agents that 
have been evaluated by the PPTP, and we discuss the preclinical and clinical 
development of these for the treatment of osteosarcoma. We further demonstrate 
that committed resources for hypothesis-driven drug discovery and development 
are needed to yield clinical successes in the search for new therapies for this 
pediatric disease.