BACKGROUND: End-stage renal disease (ESRD) in patients with type 2 diabetes mellitus (DM) is associated with a bleak prognosis. The life span of patients with DM who have undergone renal transplantation or who are undergoing dialysis is up to 30% shorter than that of individuals in the general population. Preventing or delaying the progression of renal disease from microalbuminuria to nephropathy, and ultimately, to ESRD is thus a crucial goal of DM management. OBJECTIVE: This article reviews the growing worldwide problem of type 2 DM and ESRD, the renoprotective benefits of angiotensin II (AII) antagonists (AIIAs) such as losartan in patients with or without type 1 or 2 DM, potential mechanisms of renoprotection of AIIAs beyond blood pressure (BP) control, and the clinical-practice implications of available megatrials. METHODS: Articles included in this review were identified using a MEDLINE search for English-language studies published between 1990 and 2003 and included the search terms diabetic nephropathy, type 2 diabetes mellitus, microalbuminuria, proteinuria, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, and cardiovascular disease. Articles describing major clinical trials, new data, or new mechanisms pertinent to the management of type 2 DM were selected for review. RESULTS: Currently, AIIAs such as losartan represent the only evidence-based treatment strategy for patients with type 2 DM and proteinuria. The Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA-2) study, the Reduction of End Points in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study, and the Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT) indicate that AIIAs postpone the progression of type 2 diabetic renal disease at all stages, ranging from microproteinuria to overt nephropathy and ESRD, RENAAL showed that losartan improves renal outcomes in patients with type 2 DM and nephropathy over and above that attributable to BP control alone. The renoprotective effect of losartan corresponded to an average delay of 2 years in the need for dialysis or kidney transplantation. CONCLUSIONS: AIIAs such as losartan should perhaps be considered mandatory therapy in patients with diabetic nephropathy and should complement existing management strategies, such as reduced dietary protein intake, strict blood glucose control, and standard antihypertensive therapy. Collectively, these measures should improve survival and quality of life and reduce the health care burden of managing patients with diabetic nephropathy.