Though type 2 diabetes (T2D) is a multifactorial syndrome of metabolic dysregulation, current pharmacologic strategies for T2D are focused on the progressive decline in insulin secretory dysfunction in conjunction with diminished tissue responses to insulin. Notwithstanding pancreases and peripheral tissues including skeletal muscles and adipose tissues, the liver is also largely responsible for glucose homeostasis through increasing or decreasing not only glucose output, so called hepatic glucose production (HGP), during postabsorptive (4 or 5 hours after meal ingestion) and fasting (8 or 10 hours after meal) but also glucose uptake during (4 hr after feeding) periods. Considering the glucose homeostasis regulated by the liver, potential drug targets that modulate these processes might include the glucokinase (activators), glucagon receptor (antagonists), glycogen phosphorylase (inhibitors), and other rate-controlling enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase (inhibitors). Glucokinase (GCK) is central to glucose homeostasis increasing or decreasing glucose output and uptake during feeding, postabsorptive, and fasting. Regarding the horm one, glucagon is the key target hormone to overcome the uncontrolled excessive postabsorptive and fasting HGP as well as insulin resistance in the context of progressive islet dysfunction. In the process of unrestrained HGP, glycogen phosphorylase, glucose-6-phosphatase and fructose-1,6-bisphosphatase are the enzyme targets for controlling the increased rates of gluconeogenesis and glycogenolysis. In this symposium, we’d like to show the hormonal physiology and biochemical or molecular mechanism of glucose homeostasis in the liver. And the potentials for new drug candidate and current status of drug development are also discussed.