Arteriolosclerosis (microvascular disease) may have a key role not only in driving salt-sensitive hypertension but also in mediating the development of chronic kidney disease, vascular dementia, stroke and coronary heart disease. In this paper, we review the evidence that these latter conditions result from the altered autoregulation that occurs when arterioles become diseased. We also discuss the increasing evidence that dietary intake of sugars rich in fructose may be driving the development of microvascular disease as a consequence of raising intracellular uric acid. We hypothesize that the treatment of microvascular disease may require a multifaceted approach by utilizing agents which aim at blocking of the renin-angiotensin system, reducing oxidative stress, stimulating endothelial nitric oxide production and lowering uric acid levels. Paradoxically, agents that only stimulate nitric oxide, such as oestrogens, may increase the risk of poor outcomes if microvascular disease is not reversed.