Patients with type 2 diabetes mellitus often begin treatment by taking oral agents, usually metformin or a sulfonylurea, and then progress to the combination of these two agents. Most patients often require three or more agents or a change to an insulin regimen. However, no guidelines are available to aid the clinician in the decision-making process for selecting the third agent. Many options are available for additional therapy, including thiazolidinediones, intermediate- and long-acting insulins, exenatide, and dipeptidyl peptidase-4 inhibitors. Although the American Diabetes Association recommends metformin as first-line therapy, it does not give exact specifications for second- and third-line agents but only summarizes clinical data and options about each therapeutic drug class. Guidelines from the American College of Endocrinology and American Association of Clinical Endocrinologists recommend several options depending on the patient's hemoglobin A(1c) level. Therefore, a standard of care cannot be provided; rather, clinicians must evaluate each patient to ascertain that patient's optimum therapy. In doing so, clinicians need to be familiar with the efficacy, safety, and cost of each agent.