In addition to its central role in the development of microvascular complications, hyperglycemia plays an important role in the pathogenesis of type 2 diabetes mellitus (T2DM) by means of glucotoxicity. Thus, effective glycemic control not only reduces the incidence of microvascular complications but also corrects the metabolic abnormalities that contribute to the progression of the disease. Progressive β-cell failure and multiple side effects, including hypoglycemia and weight gain, associated with many current therapies present obstacles to the achievement of optimal and durable glycemic control in subjects with T2DM. Most recently, inhibitors of the renal sodium-glucose cotransporter have been developed to reduce the plasma glucose concentration by producing glucosuria. Because the mechanism of action of these oral antidiabetic agents is independent of β-cell function and tissue sensitivity to insulin, they improve glycemic control while avoiding hypoglycemia and promoting weight loss. In this review, we summarize the available data concerning the mechanism of action, efficacy, and safety of this novel antidiabetic class of therapeutic agents.