G-protein coupled receptors (GPCRs) comprise the largest and most diverse family of membrane receptors in the human genome, relaying information from a vast array of external stimuli. GPCRs are targets for approximately 30% of all current therapeutic agents. Recently some GPCRs have been shown to mediate part of their effects through activation of AMP-activated protein kinase (AMPK), a sensor of whole body energy status that plays a pivotal role in whole body energy balance by integrating signals in the periphery and central nervous system. It regulates glucose and lipid metabolism, food intake and body weight, making it an attractive target for the treatment of diseases such as type 2 diabetes and obesity. It mediates the effects of several important adipokines such as leptin and adiponectin and is thought to be responsible for the antidiabetic effects of metformin and thiazolidinediones. A diverse number of GPCRs (including adrenoceptors, cannabinoid receptors, ghrelin receptors, melanocortin receptors) modulate AMPK activity. This review focuses on the regulation of AMPK by GPCRs and signaling intermediates of GPCR signaling such as cyclic AMP and calcium, and how GPCR signaling can modulate AMPK activity by several different mechanisms, and the therapeutic implications of AMPK activation by GPCRs.