Management of type 2 diabetes mellitus (T2DM) can be challenging. Patients frequently present with poor glycemic control despite therapy. Other patients may be nonadherent or resistant to continuing their treatment when confronted with undesirable adverse effects, such as weight gain, that are associated with many conventional therapies. Incretin-based therapies developed to treat patients with T2DM, including oral dipeptidyl peptidase-4 inhibitor agents or glucagon-like peptide-1 agonists, offer the potential of sustained glycemic control for many patients without the adverse events associated with other classes of antihyperglycemic medications. Available safety data from clinical trials indicate that incretin-based therapies have weight-neutral or weight-reducing effects, with no apparent adverse impact on other important safety parameters, such as cardiovascular disease. The integration of these therapies into treatment algorithms, as highlighted in three case presentations, will increase treatment options for patients with T2DM.