In 1962 Remensnyder1 and associates described how the sympathetic vasoconstrictor activity elicited by muscle contractions was overcome in the active muscles, allowing for a blood supply that matched the metabolic demands. NO and ATP have been discussed as possible blockers of the norepinephrine (NE) mediated vasoconstriction. The site has been proposed to be either the nerve terminal or the alpha receptor. The latest research data support an action at the alpha receptor level and the possibility that plasma ATP via a P2Y activation may explain the sympatolysis. Recently an experimental tool has become available to elevate the sympathetic nerve activity. It is named tyramine and it can be used in humans. This opens for studies of the efficiency of the functional sympatolysis during exercise in the active limbs at various healthy and diseased stages as well as the impact of the active muscles’ training status. In ageing sedentary men, functional sympatolysis and muscle blood flow is impaired compared to young men. However, regular physical activity can prevent this age related impairment in muscle blood flow and functional sympatholysis. Even in young subjects, a two-week inactivation period causes a reduced ability for sympatolysis. Patients with well controlled type 2 diabetes or essential hypertension also exhibit impaired functional sympatolysis. In the latter group, two months of elevated physical activity normalized the muscle perfusion and functional sympatholysis during exercise. Thus, the role of regular exercise for a maintained sympatolysis capacity is clear, but it is too early to draw a conclusion as to whether loss of functional sympatolysis is a primary event or secondary to a systemic capacity that is too low to produce an ample blood flow.