Insulin-independent diabetes is a disease characterized by insulin resistance and the patient's concomitant inability to compensate by exaggerated insulin secretion. A primary abnormality in the plasma membrane of the afflicted cells may cause both of these phenomena. Recent studies investigating the mechanism of action of sulfonylurea drugs show that these agents probably exert their antidiabetic action by increasing insulin sensitivity and ameliorating the insulin resistance, rather than by increasing insulin secretion. Dietary treatment alone, though effective in lowering the FPG level, does not ameliorate the insulin resistance of insulin-independent diabetes mellitus. Thus, sulfonylurea drugs appear to be rational therapeutic agents for the treatment of this form of diabetes. Clinical studies confirm the beneficial effects of these drugs in controlling the hyperglycemia of insulin-independent diabetes. Major unresolved questions are (1) Why do primary and secondary failures occur? (2) Is the underlying membrane abnormality progressive? (3) How long are sulfonylureas effective? (4) What is the mechanism of the membrane disturbance and how do sulfonylureas ameliorate it? (5) Do sulfonylureas drugs cause cardiovascular toxicity? The answers to these questions will provide further insight into our understanding of insulin-independent diabetes and will lead to the development of better drugs for its treatment. In the meantime, sulfonylureas are rational agents for the therapy for this disorder, if they are used appropriately.