Sulfonylureas are still largely used for treatment of type 2 diabetic patients, and they still occupy a central position in many international therapy guidelines. More recently concern has been raised with respect to possible adverse effects associated with the use of these agents. Sulfonylureas are, indeed, believed to favor the development of hypoglycemia, to accelerate beta cell apoptosis and beta-cell exhaustion, and to impair endothelial function with increased risk for ischemic complications. However, because of the intrinsic pathogenetic heterogeneity of type 2 diabetes, sulfonylureas are likely to remain a therapeutic option. Careful choice of a specific sulfonylurea should be made on the basis of efficacy, safety, convenience, tissue specificity, and neutrality with respect to the beta cell. In this review the advantage:disadvantage ratio of available sulfonylureas is analyzed with the purpose of providing a critical clinical appraisal of the role of sulfonylureas in the modern treatment of type 2 diabetes.