Recent data have supported the view that supplemental arginine could alleviate the initiation and development of endothelial dysfunction and also shown that it may reduce the risk of type 2 diabetes. One important finding is that these effects may indeed vary as a function of the amount of arginine, its form and notably the metabolic status of the population. Some studies have shown that low doses of slow-release arginine are better used for nitric oxide synthesis and beneficial in individuals with abnormal arginine metabolism/bioavailability. Pathophysiological data in rodents have emphasized the importance of arginase activation during the development of cardiometabolic risk, which lends credence to a potential benefit for arginine supplements. Likewise, epidemiological evidence suggests that alterations to arginine bioavailability are important regarding the cardiometabolic risk. However, other metabolic mechanisms linked to the multiple pathways of arginine metabolism may also play a role. Further studies are needed to confirm and analyze how and when supplemental arginine is beneficial to cardiometabolic health.