AMP-activated protein kinase (AMPK) is master regulator of energy balance through suppression of ATP-consuming anabolic pathways and enhancement of ATP-producing catabolic pathways. AMPK is activated by external metabolic stresses and subsequently orchestrates a complex downstream signaling cascade that mobilizes the cell for efficient energy production. AMPK has emerged as a key kinase driving lipid oxidation in skeletal muscle and this function has important implications for exercise adaptations, as well as metabolic defects associated with obesity.