Over the past four decades, several molecular mechanisms have been implicated in glucose-mediated vascular damage: increased flux through the polyol pathway, accumulation of advanced glycation endproduct precursors, activation of protein kinase C isoforms, and increased hexosamine pathway activity. Each of these mechanisms has been studied independently of the others, and there has been no apparent common element linking them. Recent discoveries have made clear that all of these seemingly unrelated mechanisms arise from a single, hyperglycemia-induced process: the overproduction of reactive oxygen species by the mitochondrial electron transport chain.