Three decades ago a revolutionary idea ascribing to dysfunctional endothelia some manifestations of diabetes was born, the Steno hypothesis. Here I briefly outline the accomplishments made in the past 15 years to buttress this hypothesis. Those include development of novel technological platforms to examine microcirculatory beds, deeper understanding of patterns of microvascular derangement in diabetes, pathophysiology of nitric oxide synthesis and availability, nitrosative and oxidative stress in diabetes, premature senescence of endothelial cells and the role of sirtuin 1 and lysosomal dysfunction in this process, state of endothelial glycocalyx and endothelial progenitor cells in diabetes. These pathophysiologic findings may confer some therapeutic benefits.