Hypoxia is arguably the most well established characteristic of solid tumors that has yet to be effectively targeted therapeutically, and it is a significant obstacle to the successful treatment of cancer. Hypoxia is a reduction in the normal level of tissue oxygen that occurs in tumors due to poor blood flow and the aberrant development of new blood vessels. In response to hypoxia, cancer cells take particular advantage of their ability to activate the hypoxia-inducible factor 1 (HIF-1) transcription factor. HIF-1 increases the expression of genes that promote survival and angiogenesis, and it is associated with poor prognosis and resistance to therapy in various types of cancer. As a result, inhibiting the activity of hypoxia-inducible factors that stimulate tumor growth is currently a major objective of anticancer therapy; most notably the use of antibodies and tyrosine kinase inhibitors to block VEGF activity. While these agents display antitumor activity, they do not markedly inhibit tumor growth or induce massive tumor regression. Therefore, new strategies are needed to inhibit the expression of hypoxia-inducible genes that stimulate tumor growth. The current focus of my lab is to develop novel approaches to target the hypoxic tumor microenvironment. Our goal is to understand the complex signaling networks that control hypoxia-mediated therapeutic resistance in solid tumors and translate these basic concepts to clinical applications that will directly impact patient care.