The hyperdynamic circulatory syndrome observed in chronic liver diseases is a great example of research that originated from clinical observations and progressed in the last 50 years from the patient to the experimental laboratory. Our knowledge has evolved from the patient to the molecule, using experimental models that serve as a source for understanding the complex pathophysiological mechanisms that govern this complex syndrome. We now know that progressive vasodilatation is central to the detrimental effects observed in multiple organs. Although nitric oxide has been shown to be the primary vasodilator molecule in these effects, other molecules also participate in the complex mechanisms of vasodilatation. This review summarizes three major areas: first, clinical observation in patients; second, experimental models used to study the hyperdynamic circulatory syndrome; and third, the vasodilator molecules that play roles in vascular abnormalities observed in portal hypertension.