Type II diabetes is characterized by elevated serum glucose levels and altered lipid metabolism due to peripheral insulin resistance and defects of insulin secretion in the pancreatic β-cells. While some cases of obesity and Type II diabetes result from genetic dysfunction, the increased worldwide incidence of these two disorders strongly suggest that the contribution of environmental factors such as sedentary lifestyles and high-calorie intake may disrupt energy balance. AMP-activated protein kinase and its upstream kinase liver kinase B1 are conserved serine/threonine kinases regulating anabolic and catabolic metabolic processes, therefore representing attractive therapeutic targets for the treatment of obesity and Type II diabetes. In this review, we will discuss the advantages of targeting the liver kinase B1/AMP-activated protein kinase pathway for the treatment of metabolic diseases.