Sulfonylureas and similarly acting rapid insulin secretagogues have long been available to manage type 2 diabetes. These agents have a well understood mechanism of action and are in large part well tolerated. However, sulfonylurea therapy is unlikely to sustain adequate long-term glycemic control and has potential side effects, including hypoglycemia and weight gain. Additional concerns exist regarding detrimental effects of certain sulfonylureas on ischemic preconditioning and cardiac outcomes. Fortunately, newer agents such as glimepiride appear less likely to adversely affect the myocardium. These agents can often be used successfully as one component of combination therapy for diabetes management.