In response to hypoxia, mammalian cells attempt to restore oxygen homeostasis by a number of physiologic adjustments. Many of these processes are regulated in whole or in part by a transcription factor complex, known as the Hypoxia-inducible Factor (HIF). Hypoxia is an early pathophysiological manifestation of the macroangiopathic complications occurring in e.g. coronary heart disease, stroke, and peripheral vascular disease in patients with type 2 diabetes. Moreover, as they expand, solid tumors can rapidly outgrow the oxygen carrying capacity of the local vasculature, rendering the core of the tumor mass hypoxic. Our laboratory has investigated the mechanism of signal transduction and gene regulation in hypoxic cells. The HIF-1 transcription factor complex contains a subunit, HIF-1alpha, which is one of the most short-lived proteins known under normoxic conditions, being targeted for proteasomal degradation by the von Hippel-Lindau tumor suppressor gene product (pVHL). Upon stabilization against degradation another critical step in the hypoxia signaling cascade is derepression of transactivation function of HIF, and conditional recruitment of transcriptional coactivator proteins, a step that is regulated by an intricate mechanism involving oxygen-dependent posttranslational modification. Oxygen availability is also an important parameter in regulation of the cell differentiation status. The lecture will address important mechanisms relevant for maintenance of an immature (stem cell-like) cell phenotype via transcriptional regulation by HIF and Notch transcription factors. In addition, our laboratory has investigated in neuroblastoma tumor cells as well as in clinical material the molecular mechanism by which hypoxia and the HIF system, in addition to inducing pro-angiogenic responses, induce de-differentiation of neuroblastoma cells from a highly differentiated phenotype expressing high differentiation markers of the sympathetic nervous system. In addition, hypoxia is an important inducing stimulus of epithelial-mesenchymal transition, linking hypoxia to tumor metastasis, and the critical role of HIF in this process will be discussed.