The risk of cardiovascular disease is significantly higher in patients with long-term uremia than in otherwise healthy adults. In addition, the risk is greater than what would be predicted from classic vascular risk factors. This is true even before patients proceed to dialysis. Although the reasons for this accelerated vascular disease are unknown, transendothelial transport of lipids and other macromolecules in both large vessels and the microcirculation has been implicated in the generation of cardiovascular disease. Furthermore, endothelial cell dysfunction is widely accepted as a cardinal feature of both modest and dialysis-dependent uremia, and is regarded as a critical step in the initiation of this aggressive pathology. This overview considers the severity of the clinical problem, the nature of the vascular endothelium, microvascular permeability (and the measurement thereof) as a functional property of the endothelium, and the in vitro and in vivo evidence for endothelial dysfunction in uremia.