This review presents recent concepts of how beta-agonists affect glucose homeostasis by modulating insulin secretion, liver metabolism, and uptake of glucose into muscle, with attention to the influence of hypoglycemia on beta-agonist sensitivity and the effects of beta(3)-adrenergic receptor (beta(3)AR) polymorphisms on adipocyte metabolism. Specific beta(2)-agonist effects on the pancreatic beta 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 beta(2)ARs on pancreatic beta 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 beta-agonist sensitivity. Scrupulous avoidance of hypoglycemia over many weeks to months can restore beta-agonist sensitivity and improve detection of hypoglycemia. beta-agonists have also been employed to prevent hypoglycemia. beta-agonists can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores. While beta(1)ARs and beta(2)ARs mediate many of these actions, it is likely that beta(3)ARs in the adipocyte membrane also play an important role. Specific beta(3)AR subtypes have been associated with obesity and the metabolic syndrome.