AMP-activated protein kinase (AMPK) is a major energy sensor that regulates cellular and whole body energy balance. AMPK has critical roles in reprogramming metabolism and regulating growth. This chapter summarizes the recent breakthroughs in AMPK function in the liver, focusing on a number of newly identified downstream effectors.Hence, understanding the control of cellular processes by AMPK could guide us to identify and improve preventive and therapeutic strategies for liver diseases. Recently, AMPK has attracted widespread interest as a potential therapeutic target for metabolic disorders including fatty liver disease and cancer. Introduction Over the recent years, the AMP-activated protein kinase (AMPK) has attracted a large interest due to its major role in the regulation of energy metabolism. AMPK isa highly evolutionary conserved serine/threonine kinase in all eukaryotes[1]. AMPKfunctions as a signaling hub to coordinate metabolic pathways in order to balance nutrient supply with energy demand at the cellular, organ and organism levels[2]. AMPK protects cells from cellular energy imbalance imposed by inhibition of ATP synthesis (glucose deprivation, hypoxia and metabolic poisons) or stimulation of ATP consumption (exercise and biosynthetic pathways). AMPK is sensitive to the relative changes in the cellular ratios of ADP to ATP and AMP to ATP and initiates metabolic changes to reprogram metabolism by inhibiting nonessential anabolic ATP-consuming processes while stimulating ATP-delivering catabolic pathways. The regulation of cellular energy metabolism by AMPK activation is achieved by acute phosphorylation of key enzymes in carbohydrate, lipid and protein metabolism for short-term effects[2], as well as phosphorylation of transcription factors for longer-term regulatory effects[3].Given these properties, it is not surprising that AMPK has emerged as an attractive therapeutic target for pathological conditions characterized by abnormal energy utilization, such type 2 diabetes and related metabolic disorders[4]. Activation of AMPK by various anti-diabetic drugs has further reinforced the idea that AMPK activators could be used for the treatment of metabolic diseases. It is now recognized that pharmacological activation of AMPK improves blood