This article highlights the use of antidiabetic agents, including insulin. Medical nutrition therapy (MNT) and physical activity are the cornerstones of management of type 2 diabetes. The progressive nature of type 2 diabetes requires use of one or more oral agents and eventually insulin, along with MNT and physical activity. The American Association of Clinical Endocrinologists and the European Association for the Study of Diabetes have recommended a lower hemoglobin A1c target of <6.5%, and many health care providers strive to achieve normalization of blood glucose. Achievement of these goals often prompts providers to consider combination therapy to target different pathogenic mechanisms and manage both fasting and postprandial blood glucose levels. Maintenance of glycemic control over the lifespan of a patient with diabetes is overwhelmingly likely to require combination therapy with oral diabetes medications. The UK Prospective Diabetes Study reported that <50% of patients maintained glycemic control on MNT or monotherapy with oral agents at 3 years, and that number dropped to <25% at 9 years. Newer agents and insulins have become available since the UK Prospective Diabetes Study was completed and have enhanced our armamentarium of therapeutics for treatment of diabetes.