The complications of diabetic microangiopathy have been well documented clinically for many years; however, the specific cellular mechanisms that lead to the dysfunction of small vessels in diabetes are unknown. Histopathological studies on diabetic microangiopathy have established thickened vascular basement membrane as one of the first and foremost structural abnormalities. Evidence suggests that this fundamental structural lesion develops, at least in part, from excess accumulation of basement membrane material in the vessel walls. Several vascular basement membrane components have been identified whose expression is up-regulated in diabetes. Enzymes responsible for the degradation of basement membrane components have also been reported to exhibit reduced activity. Strategies are being developed to regulate the abnormal accumulation of extracellular matrix (ECM) components in diabetic microangiopathy. In experimental diabetes, aldose reductase inhibitors have been found to be effective in preventing vascular basement membrane thickening when applied soon after the onset of hyperhexosemia. Clinical trials have been initiated with inhibitors of protein kinase C, an enzyme that up-regulates the synthesis of ECM components in diabetes. Currently, gene therapy strategies are also being developed to inhibit specific gene expression responsible for excess ECM synthesis in diabetes. Recent studies in the authors' laboratory have shown the applicability and efficacy of antisense oligonucleotides toward reducing vascular basement membrane component synthesis. Several gene regulatory approaches are currently being developed to modulate and prevent vascular basement membrane component synthesis. Such strategies may help identify key events that underlie the complex developmental stages of diabetic microangiopathy.