Tissue hypoxia occurs where there is an imbalance between oxygen supply and consumption in both, solid tumors as a result of exponential cellular proliferation and in atherosclerotic diseases as a result of inefficient blood supply. Hypoxia-inducible factor 1 (HIF-1) is central in normal angiogenesis and cancer angiogenesis. HIF-1 is a transcriptional activator composed of an O2- and growth factor-regulated HIF-1α subunit and a constitutively expressed HIF-1β subunit. Upon activation, HIF-1 drives the expression of genes controlling cell survival and governing the formation of new blood vessels. A better understanding of the regulation of HIF-1α levels by the receptor tyrosine kinases/phosphatidylinositol 3-kinase signaling pathway and by the HIF prolyl hydoxylases has provided new insights into the development of anticancer and revascularization therapeutics. We will focus on the potential of a new pharmacology for regulating HIF pathways in both, cancer and ischemic cardiac diseases. The consequences of the switch of HIF activation in these two disease states and the signaling pathway overlap that atherosclerosis and cancer angiogenesis share are discussed. © 2004 Wiley-Liss, Inc.