Once-weekly (OW) glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated improved glycemic control in patients with type 2 diabetes (T2D), and some have a number of other benefits, including weight loss, improvements in blood pressure and lipid profiles, and cardiovascular protection. They also provide a therapy option with a low risk of hypoglycemia, an attractive choice for many patients. Molecular structure and pharmacokinetic properties vary among GLP-1 RAs, with some more closely related than others to native glucagon-like peptide-1 (GLP-1). OW GLP-1 RAs have various modifications to their molecular structure that make the molecules resistant to degradation by dipeptidyl peptidase-4 (DPP-4), increasing the half-life of these drugs and making them suitable for OW administration. These differences in the molecular structures and pharmacokinetic properties between the various OW GLP-1 RAs help to explain the differences in efficacy, mechanisms, and safety profiles among the drugs, and these considerations can help primary care physicians to optimize prescribing practices.