Combination sulfonylurea-insulin therapy for patients with diabetes mellitus has been evaluated by numerous investigators with various experimental designs. Much of the data are conflicting, and clear conclusions do not seem justified. Insulin-sulfonylurea therapy is probably not clinically useful in most patients with insulin-dependent diabetes mellitus. Most non-insulin-dependent diabetic (NIDDM) patients are also unlikely to have meaningful improvement in glycemic regulation on insulin-sulfonylurea therapy. A subset of NIDDM patients who are mildly to moderately obese, have adequate endogenous insulin secretory reserve, and are in poor glycemic regulation (fasting plasma glucose greater than 11 mM and/or HbA1 greater than 10%), despite twice-daily insulin administration of greater than 70 U/day, may show significant improvement of glycemic regulation and/or decreases in insulin daily dose on insulin-sulfonylurea therapy. The mechanisms by which insulin-sulfonylurea therapy improves glycemic regulation and decreases insulin requirements involve an increase in endogenous insulin secretion and possibly some extrapancreatic actions of the sulfonylureas on muscle and liver.