The AMP-activated protein kinase (AMPK) was initially considered as an intracellular fuel gauge activated by decreased ATP levels and/or an elevated AMP/ATP ratio due to cellular and environmental stress such as heat shock, hypoxia and ischemia. Accumulating evidence suggests that AMPK not only controls the whole body energy homeostasis including fatty acid oxidation, glucose and glycogen metabolism, but also modulates cardiac electromechanical function, protein synthesis and cell growth through EF2 and TSC2/mTOR pathways. In addition, AMPK participates in a cascade of biological events from food intake control to cardiac regulation elicited by hormones and adipokines such as leptin and adiponectin. AMPK has been demonstrated to play an essential role in cellular energy metabolism and ventricular function in ischemia-reperfusion. Mutation in AMPKγ subunit encoding gene PRKAG2 is believed to be responsible for the Wolff-Parkinson-White syndrome re-entry arrhythmia, indicating a likely role of AMPK in cardiac electromechanical regulation. A number of physiological and pharmacological factors or drugs beneficial to cardiac defects in hypertrophic cardiomyopathy, obesity and diabetes mellitus have been shown to act, at least in part, through AMPK activation, thus making AMPK an attractive target for therapeutic intervention against certain cardiac and metabolic disorders.