PGC-1α is a transcriptional coactivator that regulates VEGF and angiogenesis independently of the hypoxia-inducible factor (HIF) pathway. Ischaemia of the heart, brain, and limbs is a major cause of morbidity and mortality. Hypoxia stimulates VEGF and other angiogenic factors, leading to neovascularization. PGC-1α is induced by nutrient and oxygen deprivation and regulates VEGF expression and angiogenesis in muscle cells. PGC-1α knockout mice show impaired blood flow recovery after ischaemia, while transgenic expression of PGC-1α in skeletal muscle is protective. PGC-1α induces VEGF without involving the HIF pathway, instead coactivating the orphan nuclear receptor ERR-α on conserved binding sites in the VEGF gene. PGC-1α and ERR-α regulate a novel angiogenic pathway that delivers oxygen and substrates. PGC-1α may be a therapeutic target for ischaemic diseases. PGC-1α is a potent modulator of oxidative metabolism and regulates oxidative phosphorylation, mitochondrial biogenesis, and respiration. PGC-1α is induced by nutrient and oxygen deprivation and regulates a wide programme of genes involved in neovascularization. PGC-1α induces angiogenesis in vivo, as shown by increased capillary density and blood flow recovery in transgenic animals. PGC-1α is required for the normal vascular response of skeletal muscle to ischaemia. PGC-1α does not affect functional VEGF signalling in endothelial cells. PGC-1α induces VEGF independently of the HIF pathway. PGC-1α coactivates ERR-α, which is involved in fatty acid oxidation and oxidative phosphorylation. ERR-α recognizes conserved DNA sequences in the VEGF gene and is coactivated by PGC-1α to induce VEGF transcription. PGC-1α/ERR-α pathway mediates exercise-induced neovascularization. PGC-1α is also robustly induced by exercise and mediates known responses to exercise such as fibre-type switching and mitochondrial biogenesis. The PGC-1α/ERR-α pathway provides an opportunity for modulating transcriptional regulators that coordinate signals for vascularization. PGC-1α is a mediator of signalling in response to nutrient and oxygen deprivation, and regulates VEGF and other angiogenic factors to elicit neovascularization in vivo. PGC-1α is not essential in embryonic vascularization. Angiogenesis in the adult occurs in physiological and pathological contexts. PGC-1α is a key regulator of angiogenesis in response to ischaemia. PGC-1α/ERR-α pathway also mediates exercise-induced neovascularization. Angiogenesis is crucial to tumour progression and metastasis. The interface ofPGC-1α is a transcriptional coactivator that regulates VEGF and angiogenesis independently of the hypoxia-inducible factor (HIF) pathway. Ischaemia of the heart, brain, and limbs is a major cause of morbidity and mortality. Hypoxia stimulates VEGF and other angiogenic factors, leading to neovascularization. PGC-1α is induced by nutrient and oxygen deprivation and regulates VEGF expression and angiogenesis in muscle cells. PGC-1α knockout mice show impaired blood flow recovery after ischaemia, while transgenic expression of PGC-1α in skeletal muscle is protective. PGC-1α induces VEGF without involving the HIF pathway, instead coactivating the orphan nuclear receptor ERR-α on conserved binding sites in the VEGF gene. PGC-1α and ERR-α regulate a novel angiogenic pathway that delivers oxygen and substrates. PGC-1α may be a therapeutic target for ischaemic diseases. PGC-1α is a potent modulator of oxidative metabolism and regulates oxidative phosphorylation, mitochondrial biogenesis, and respiration. PGC-1α is induced by nutrient and oxygen deprivation and regulates a wide programme of genes involved in neovascularization. PGC-1α induces angiogenesis in vivo, as shown by increased capillary density and blood flow recovery in transgenic animals. PGC-1α is required for the normal vascular response of skeletal muscle to ischaemia. PGC-1α does not affect functional VEGF signalling in endothelial cells. PGC-1α induces VEGF independently of the HIF pathway. PGC-1α coactivates ERR-α, which is involved in fatty acid oxidation and oxidative phosphorylation. ERR-α recognizes conserved DNA sequences in the VEGF gene and is coactivated by PGC-1α to induce VEGF transcription. PGC-1α/ERR-α pathway mediates exercise-induced neovascularization. PGC-1α is also robustly induced by exercise and mediates known responses to exercise such as fibre-type switching and mitochondrial biogenesis. The PGC-1α/ERR-α pathway provides an opportunity for modulating transcriptional regulators that coordinate signals for vascularization. PGC-1α is a mediator of signalling in response to nutrient and oxygen deprivation, and regulates VEGF and other angiogenic factors to elicit neovascularization in vivo. PGC-1α is not essential in embryonic vascularization. Angiogenesis in the adult occurs in physiological and pathological contexts. PGC-1α is a key regulator of angiogenesis in response to ischaemia. PGC-1α/ERR-α pathway also mediates exercise-induced neovascularization. Angiogenesis is crucial to tumour progression and metastasis. The interface of