Type 2 diabetes affects over 25 million people in the United States. There are many treatment options for patients with type 2 diabetes, but current treatments must be administered on a daily basis. Once-weekly exenatide, an extended-duration glucagon-like peptide-1 (GLP-1) agonist, provides an option for patients to take a drug weekly, with pharmacotherapeutic effects that are superior to twice-daily exenatide and sitagliptin and comparable to insulin glargine. The DURATION trials provide evidence that once-weekly exenatide reduces hemoglobin A1c, and may result in weight loss. Once-weekly exenatide is marketed as a 2-mg injection administered subcutaneously once every 7 days. Adverse effects of once-weekly exenatide include gastrointestinal effects, hypoglycemia, injection-site reactions, pancreatitis, and antibody development. Patients with a self history or family history of thyroid tumors should avoid using once-weekly exenatide. Delayed gastric absorption with orally administered drugs is possible, and monitoring should occur to avoid loss in therapeutic effect. Once-weekly exenatide is a new extended-duration agent with efficacy and tolerability profiles comparative to older therapies. Appropriate patients for once-weekly exenatide would be those who are concerned about weight gain, hypoglycemia, or those who do not wish to administer injections daily.