Biology of the von Hippel-Lindau/hypoxia-inducible factor (VHL-HIF) axis in the setting of hypoxia or a mutation or aberration of the VHL gene product. In normoxic conditions, HIFα is hydroxylated on specific proline residues by prolyl-hydroxylases. VHL acts as the sensor for these hydroxylated proline residues as part of the VHL-E3 ubiquitin ligase. This polyubiquitinates HIFα and marks it for degradation by the proteasome. In hypoxic conditions (or in the presence of aberrant VHL), HIFα is allowed to accumulate in the cell. It associates with HIFβ and this complex translocates to the nucleus and acts as a transcription factor binding to hypoxia response elements and upregulating oxygen-sensitive genes. These HIF-responsive genes include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor alpha (TGFα), glucose transporter-1 (GLUT1), carbonic anhydrase IX (CA-IX), erythropoietin (EPO), and others. Examples of selected receptors are given, including VEGF receptor (VEGFR), PDGF receptor (PDGFR), and the receptor for TNFα and epidermal growth factor receptor (EGFR). Shown is the downstream signaling for one of these receptors, VEGFR, including through the PI3 kinase (PI3K)/AKT/mTOR, p38 MAP kinase (p38MAPK), and RAS/RAF/MEK/ERK pathways. Examples of agents (including pazopanib) that impact on this cascade are given, and where they act on the pathway is shown.