Osteosarcoma patients who respond poorly to chemotherapy are at a high risk of relapse and adverse outcome. This study characterized genes predictive of poor response through the use of expression profiling on tumor samples obtained at diagnosis. The schematic model on the cover depicts a hypothesis underlying chemotherapy resistance in osteosarcoma as mediated by several genes. These genes alter proteolytic mechanisms that function in a multigenic fashion to mediate osteoclast activation, tumor survival, and a modified extracellular matrix (ECM) environment. We hypothesize that poor-prognosis tumors might progress and develop a malignant phenotype through the increased expression of oncogenic factors RAB4B, myc, and pleiotrophin and a decreased expression of proapoptotic BAX. The elevated expression of migration and invasion genes could cooperatively function to alter the ECM. The decrease in OPG and increase in bone resorption genes mediate a drive toward osteoclastogenesis. Thereafter, the destruction of bone matrix might release stored growth factors, such as TGF-β, which establish a positive feedback toward tumor progression and ECM remodeling. This model represents a starting point for further hypothesis testing to abrogate the tumor in resistant cases. For details, see the article by Mintz et al. on page 1748 of this issue.