Like other tumors, chondrosarcoma must induce neovascularity as they grow. Recent studies have demonstrated that chondrosarcoma are vascular. Since normal cartilage is a hypoxic, yet avascular tissue and since chondrosarcoma bears some phenotypic relation to cartilage, it is not clear if hypoxic pathways remain intact in these tissues. Hypoxia-inducible factor 1alpha (HIF-1alpha) is the inducible subunit of the HIF-1 transcription factor that regulates genes involved in the response to hypoxia, some of which promote neovascularity. Vascular endothelial growth factor (VEGF) is one of the genes upregulated by HIF-1 and is the primary cytokine related to angiogenesis. In this study we examined the response of chondrocytes and chondrosarcoma cell lines to hypoxia. We found that both normal and malignant chondrocytes increased HIF-1alpha protein expression in an oxygen concentration dependent manner and also increased VEGF mRNA expression in response to hypoxia. HIF-1alpha protein and VEGF mRNA decreased when chondrosarcoma cells were transfected with siRNA targeting HIF-1alpha prior to hypoxia exposure, suggesting that HIF-1alpha expression resulted in increased VEGF expression. The role of the HIF-1alpha/VEGF pathway in angiogenesis in chondrosarcoma in vivo and its usefulness as a target for antiangiogenic treatment strategies for this tumor requires further investigation.