Hypoxia-inducible factors (HIF) are ubiquitous transcription factors regulated by oxygen-dependent proteolysis, and hence rapidly mount an adaptational response to hypoxia. The HIF system is apparently more complex than initially considered in the perspective of the increasing number of HIF target genes, and the inter-relationship with various additional regulatory pathways. Regional hypoxia is believed to play a major role in renal disease. Experimental data confirm a role for HIF in renal pathophysiology. The discovery of HIF prolyl-hydroxylases as key enzymes of oxygen sensing and HIF proteolysis offer new possibilities to therapeutically target HIF. Herein, we review basic concepts of HIF regulation, and existing data on HIF activation in renal disease.