A number of factors are involved in the regulation and maintenance of vascular homeostasis. The role of the vascular endothelium has been identified almost three decades ago, and a number of lines of evidence provide solid support to the role of this tissue in modulating not only vascular tone, but also phenomena such as platelet, red blood cell aggregation and deformability. In turn, hemorheological characteristics have been proven to impact on the endothelial release of mediators and therefore on vascular tone. Both biochemical and physical stimuli are sensed by the endothelium as stimuli for the release of oxygen free radicals and nitric oxide. In particular, changes in blood viscosity have a direct effect on shear stress, which is believed to be the physiological stimulus for endothelial activation. These considerations have lead us to formulate an alternative hypothesis for the meaning of hyperviscosity in the setting of ischemic syndromes. While this hypothesis is supported by animal data, the evidence of cross-sectional human studies is controversial. This evidence is discussed in the present review.