This review presents recent concepts of how β-agonists affect glucose homeostasis by modulating insulin secretion, liver metabolism, and uptake of glucose into muscle, with attention to the influence of hypoglycemia on β-agonist sensitivity and the effects of β₃-adrenergic receptor (β₃AR) polymorphisms on adipocyte metabolism. Specific β₂-agonist effects on the pancreatic β cell result in increased insulin secretion, yet other mechanisms, such as increased glucagon secretion and hepatic effects, cause an overall increase in serum glucose and an apparent decrease in insulin sensitivity. Human studies confirm the presence of β₂ARs on pancreatic β cells. Intensive treatment of diabetes mellitus with insulin, especially in type 1 diabetes, has led to increased incidence of hypoglycemia. Repeated episodes of hypoglycemia lead to unawareness of neuroglycopenia, a major limitation to intensive treatment. Hypoglycemic unawareness is associated with reduced β-agonist sensitivity. Scrupulous avoidance of hypoglycemia over many weeks to months can restore β-agonist sensitivity and improve detection of hypoglycemia. β-agonists have also been employed to prevent hypoglycemia. β-agonists can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores. While β₁ARs and β₂ARs mediate many of these actions, it is likely that β₃ARs in the adipocyte membrane also play an important role. Specific β₃AR subtypes have been associated with obesity and the metabolic syndrome. (J Allergy Clin Immunol 2002;110:S313-7.)