Oral agents are the mainstay of pharmacologic treatment for type 2 diabetes, and physicians now have a number of agents to choose from. However, more choices translate into more complex decision making. Many patients with diabetes have associated comorbidities, and most diabetic patients will require more than 1 agent to achieve good glycemic control. This article illustrates several of the pharmacologic approaches to type 2 diabetes through 4 situations that use principles of evidence-based medicine. The scenarios also highlight some of the difficulties in choosing the optimal pharmacologic treatment regimen for individual patients. Physicians should also recognize that type 2 diabetes is a multisystem disorder that requires multidisciplinary care, including education and ongoing counseling for effective patient self-management of the disease. Finally, patient preferences are a vital component of informed decision making for pharmacologic treatment of diabetes.