The cardiovascular system helps maintain blood pressure and blood flow to the different organ systems through many elaborate mechanisms. These mechanisms include the different blood vessels, each with their own properties, as well as both neural and humoral factors. The vessels that are most relevant here are arterioles, also known as resistance vessels, as they play a significant role in regulating organ blood flow, vascular resistance, and blood pressure in many different physiological conditions, such as exercise. More specifically, the focus of this paper is the endothelial layer of the arteriolar wall and its role in attenuating sympathetic adrenergic vasoconstriction, or sympatholysis. Exercising skeletal muscle cells require an increase in blood flow to adequately meet their oxygen and nutrient demands. In order to accomplish this, there is an increase in cardiac output by the heart and also a redistribution of blood flow away from inactive regions towards active muscle cells. This critical redistribution of blood flow depends on the sympathetic nervous system, which increases in activity during contraction to cause vasoconstriction of the arterioles that supply other inactive organs except the brain. Despite this increase in sympathetic nerve activity, there is also profound vasodilation in the microvasculature of active skeletal muscle cells. It is this paradox that helps match the increase in metabolism with an increase in blood flow during exercise, and it is also this mechanism that has been coined ‘functional sympatholysis.’ Although much effort has been put into studying the mechanism through which functional sympatholysis occurs, the existing data and evidence are not sufficient to deduce a clear picture at this time. There are inconsistencies regarding the functional distribution of alpha-adrenergic receptors, the role of non-adrenergic receptors, the impact of many different metabolic factors, and finally also the contribution of non-metabolic factors. Due to such contrasting data, it is clear that further research will need to be conducted in order to obtain a concrete explanation for sympatholysis. A recent study has postulated that the process of sympatholysis may primarily involve the endothelium. This study used various manipulations that involved endothelium-dependent vasodilatory responses as well as endothelium-independent vasodilatory responses intersected with sympathetic adrenergic nerve activity to determine that only those vasodilatory agents that functioned using the endothelium were able to attenuate sympathetic adrenergic vasoconstriction. This compelling evidence has made way for further inquiry into the endothelium’s role in this very important process. Due to the fact that the greatest amount of research has been devoted to studying the contraction-related attenuated responsiveness of alpha-adrenergic receptors, a hypothetical study and its various methods are proposed in this paper. This hypothesis states that both adenosine triphosphate and flow-mediated dilation, two vasodilatory stimuli that rely on a functional endothelium, are sympatholytic agents, whereas adenosine, which acts on vascular smooth muscle to cause vasodilation, is not sympatholytic. The conclusions that might be drawn from such a study and their various implications are also discussed. Finally, the major relevancy in this topic relates to the fact that sympatholysis or impaired sympatholysis may be a factor in many metabolic and cardiovascular diseases along with exercise. Some of the diseases discussed here are type II diabetes, hypertension, and chronic myocardial infarction. A concrete understanding of the mechanism by which this process occurs would potentially help invent new treatment plans and prevention. At this point, it seems probable that the endothelium does play a significant role in sympatholysis, but whether it is the primary dictator and whether there are also other influences that are absolutely essential still remains relatively uncertain.