Type 2 diabetes mellitus manifests in an insulin-resistant individual when pancreatic beta-cells are unable to produce sufficient insulin to overcome insulin resistance in the muscles and liver. There is a growing body of evidence that the thiazolidinedione (TZD) class of antidiabetic agents rejuvenates beta-cells and improves their function. When combination therapy with a sulfonylurea drug and metformin fails, treatment with a TZD increases C-peptide concentrations, reflecting improvement in beta-cell function. Further evidence of TZD-induced preservation of beta-cell function is documented by the findings of several recent trials in diabetes prevention. This apparent ability of TZDs to rejuvenate beta-cells, in addition to improving insulin resistance and glycemic control, is a compelling reason to use these agents as initial therapy for type 2 diabetes.