The role of vitamin D in calcium-phosphorus metabolism and its fundamental importance for growth and the maintenance of skeletal integrity throughout life have long been acknowledged. Furthermore, and for many years now, a considerable body of experimental, clinical and epidemiological evidence has shed light on other important functions of the vitamin D biological system in relation to cell differentiation and growth, modulation of the immune response, control of other hormonal system activity and, not least, its ability to interfere with major cardiometabolic risk factors and to influence the development and progression of many cardiovascular disorders. In a previous review published in this very journal in 2019, the composition and functions of the vitamin D biological system, the criteria for measuring and assessing the vitamin’s nutritional status, and the results of multiple studies on the possible relationships between vitamin D’s nutritional status and metabolic and cardiovascular alterations were discussed extensively, including an examination of possible pathophysiological connections vitamin D. In the years since that date, recent clinical and epidemiological research has been aimed at both obtaining further confirmation of what has been observed through previous clinical and observational studies, and above all at attempting to demonstrate the possible “causal” role of vitamin D deficiency in relation to the aforementioned disease conditions through controlled and randomised trials with high quality scientific criteria. This review therefore endeavours to selectively focus on the results of these latest studies and to discuss the scientific basis for the use of vitamin D supplementation for prophylactic or therapeutic purposes.