The increased number of cases of type 2 diabetes mellitus (both diagnosed and undiagnosed) parallels the current epidemic of obesity in the United States. Despite receiving treatment, many patients do not achieve established therapeutic goals. Type 2 diabetes mellitus is a progressive disease characterized by multiple abnormalities that extend beyond β-cell dysfunction and insulin resistance. Incretin-based agents, including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, have become important options in the therapeutic paradigm for patients with type 2 diabetes mellitus. The author reviews physiologic mechanisms of the incretin system and discusses the practical application of GLP-1 receptor agonists and DPP-4 inhibitors in improving GLP-1 dynamics in patients with type 2 diabetes mellitus.