Oncogenic signals act through multiple parallel pathways to activate HIF and its target genes. In addition to regulation by hypoxia, hydroxylation of hypoxia inducible factor (HIF)-α may be influenced by metabolic and redox signals. In cancer, all of these micro-environmental stresses can inhibit hydroxylation leading to accumulation of HIF. Oncogenic signals also impinge on the HIF pathway at many other points, including transcription, translation, post-translational modification and pVHL-mediated degradation of HIF-α polypeptides. In addition, oncogenic signals activate many HIF target genes directly.