The finding that AMP-activated protein kinase (AMPK) was activated by exercise in skeletal muscle, reported by Winder and Hardie in 1996, provided the first hint that this signaling pathway might represent the elusive and long-sought system that was responsible for the metabolic changes associated with exercise. It triggered an increasing volume of research that has now largely vindicated this hypothesis although, in the usual manner of these things, it is not the whole story. As discussed in this article, it is becoming clear that the AMPK system is partly, but not entirely, responsible for the acute metabolic responses of muscle to acute exercise. It is particularly involved in the switch from the anaerobic metabolism of glycogen to oxidative metabolism of blood glucose and fatty acids. It also appears to be responsible for most, if not all, of the long-term metabolic adaptations to aerobic exercise (i.e., to endurance training), particularly the up-regulation of mitochondrial content and oxidative metabolism. Interestingly, this role is a reflection of the evolutionary origins of the kinase, because the homolog of AMPK in a single-celled eukaryote, the brewer's yeast Saccharomyces cerevisiae, is also involved in the switch from anaerobic to aerobic metabolism.