Skeletal muscle is one of the most plastic tissues in the body. Repeated exercise causes several muscle adaptations, among which the development of additional capillaries (angiogenesis) is prominent. Conversely, inactivity and some chronic diseases result in loss of muscle capillaries. Since (endurance) exercise depends on adequate O2 supply, it is reasonable to hypothesize that hypoxia occurring within muscle during exercise may provide the stimulus to angiogenesis. However, there are other potential stimuli including physical effects of increased muscle blood flow, or of muscle contraction; release of molecules such as NO that could transcriptionally activate angiogenic growth factors; and perhaps changes in the biochemical milieu of the muscle cell such as acidosis. This brief review will address evidence collected to date mostly at the molecular biological level that does in fact implicate reduced intracellular PO2 as a major stimulus to the angiogenic process resulting from exercise. In particular, it is shown that VEGF message and protein are increased in muscle with exercise, more so in hypoxia, and that HIF-1alpha correlates with VEGF as would be expected if hypoxia were the major stimulus. In addition, we show that muscle intracellular PO2 falls to very low levels during exercise (3-4 Torr), providing a degree of hypoxia compatible with a strong role for low PO2 in angiogenic growth factor response. However, the definitive experiments using acute gene manipulation to establish a cause and effect relationship between hypoxia and muscle angiogenesis remain to be performed.