Despite advances in cancer treatment, chemotherapy resistance and metastasis are major barriers to cure. Historically, the study of drug resistance and metastasis have proceeded along separate pathways. However, growing evidence has demonstrated that chemoresistance and invasiveness may be linked. We recently demonstrated that neuroblastoma cells display characteristics of mesenchymal change via multiple pathways in their transition to a drug-resistant state. The tumor microenvironment is ever-changing and experiences fluctuation in hypoxia and nutrient deprivation that can lead to epigenetic and genetic adaptations that increase invasiveness and metastasis. Study of the regulation of gene products in response to hypoxia has found the transcription factor hypoxia-inducible factor 1α (HIF-1α) to be involved. HIF1α is consistently implicated in cancer metastasis and its overexpression is a marker of poor prognosis. This holds true in osteosarcoma and breast cancer as well. It is involved in the activation of numerous cellular processes including resistance against apoptosis, over-expression of drug efflux membrane pumps, vascular remodeling, angiogenesis and metastasis, making it a target for cancer therapy research.