More than 8 million Americans are afflicted with non-insulin-dependent diabetes mellitus (NIDDM), a complex disease process characterized by insulin resistance and impaired insulin secretion. Diet and exercise continue to be the cornerstones of treatment. Most patients, however, require the addition of an oral sulfonylurea agent to achieve adequate glucose control. The second-generation sulfonylureas, glyburide and glipizide, are effective at lower doses and may have fewer adverse effects and drug interactions than the older, first-generation agents. For these reasons the second-generation sulfonylureas are preferred. Insulin therapy is required in patients with hyperosmolar state, infection, or other forms of stress, or in those who fail to respond to treatment with oral sulfonylurea. Some patients may benefit from the concurrent administration of insulin and an oral agent. Hypoglycemia is the greatest risk of drug therapy in elderly patients with NIDDM. This is especially true in elderly patients who are exquisitely sensitive to the effects of sulfonylureas and insulin. Treatment should, therefore, be initiated at very low doses and gradually adjusted.