Type 2 diabetes mellitus is a chronic disease characterized by insulin resistance, impaired insulin secretion, and/or increased hepatic glucose production. The mainstays of drug treatment are the oral antidiabetic agents. Insulin is usually reserved for patients who do not achieve fasting plasma glucose or A1C goals with or cannot tolerate the oral antidiabetic agents. There are 5 classes of oral antidiabetic agents available in the United States: sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and nonsulfonylurea secretagogues. They have differences and similarities with respect to their pharmacology and role in diabetes. This article reviews the pharmacology, efficacy, safety, and selection of the oral agents used to treat type 2 diabetes mellitus.