Type 2 diabetes (T2DM) is a disease of epidemic proportion associated with significant morbidity and excess mortality. Optimal glucose control reduces the risk of microvascular and possibly macrovascular complications due to diabetes. However, glycemic control is rarely optimal and several therapeutic interventions for the treatment of diabetes cause hypoglycemia and weight gain; some may exacerbate cardiovascular risk. Exenatide (synthetic exendin-4) is a glucagon- like peptide-1 receptor (GLP-1R) agonist developed as a first-in-class diabetes therapy. This review presents an overview of the evolution of exenatide as a T2DM treatment, beginning with the seminal preclinical discoveries and continuing through to clinical pharmacology investigations and phase 3 clinical trials. In patients with T2DM, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, and enhanced satiety. In controlled phase 3 clinical trials ranging from 12 to 52 weeks, 10-mcg exenatide twice daily (ExBID) reduced mean HbA1c by -0.8% to -1.7% as monotherapy or in combination with metformin (MET), sulfonylureas (SFU), and/or thiazolidinediones (TZD); with mean weight losses of -1.2 kg to -8.0 kg. In controlled phase 3 trials ranging from 24 to 30 weeks, a 2-mg once-weekly exenatide formulation (ExQW) reduced mean HbA1c by -1.3% to -1.9%, with mean weight reductions of -2.3 to -3.7 kg. Exenatide was generally well-tolerated. The most common side effects were gastrointestinal in nature, mild, and transient. Nausea was the most prevalent adverse event. The incidence of hypoglycemia was generally low. By building upon early observations exenatide was successfully developed into an effective diabetes therapy.