Current insulin therapy still fails to safely restore near-normoglycemia in the majority of patients. Among the barriers to achieving tight long-term glycemic control with insulin in both type 1 and type 2 diabetes are an increased risk of hypoglycemia, undesired weight gain, and a failure to normalize postprandial hyperglycemia and excessive unpredictable diurnal glucose fluctuations. Amylin is a second beta-cell hormone that is cosecreted with insulin in response to meals, and is deficient in patients with type 1 and insulin-requiring type 2 diabetes. Preclinical studies indicate that amylin acts as a neuroendocrine hormone that complements the effects of insulin in postprandial glucose regulation by suppressing postprandial glucagon secretion and slowing the rate of nutrient delivery from the stomach to the small intestine. Human amylin is not optimal for replacement therapy because of its propensity to aggregate; thus, pramlintide, a soluble, nonaggregating synthetic peptide analog of human amylin, was developed that has potency at least equal to that of human amylin. In clinical studies, subcutaneous injections of pramlintide prior to meals, in addition to insulin therapy, significantly reduced postprandial glucose excursions and lowered HbA(1c) levels in patients with type 1 and type 2 diabetes. The improvement in long-term glycemic control was associated with a significant reduction in body weight and occurred without increases in total daily insulin use or in overall severe hypoglycemia event rates. Because of this unique spectrum of clinical effects, amylin replacement with pramlintide as an adjunctive therapy to insulin is a promising approach that may fulfill some of the unmet clinical needs of insulin-using patients with type 1 and type 2 diabetes.