Soluble CD40 ligand (sCD40L) is involved in the pathogenesis of risk factor-related vascular damage and has been regarded as a molecular link between inflammation, thrombosis and angiogenesis. Given the increasingly recognized theory that hypertension is in part an inflammatory disorder, the contribution of CD40/CD40L dyad is becoming one of the outstanding puzzles in the pathophysiology of hypertension. CD40/CD40L signaling appears, in fact, like a versatile pathway that vehicles information within vascular cells. Several distinct lines of investigation in the context of hypertension dealing with low-grade inflammation are now merging, with CD40/CD40L system as the missing link. As an example, recent data suggest that the vasoactive peptide angiotensin II promotes and augments the inflammatory activation induced by CD40/CD40L ligation in human vascular cells. Accordingly, sCD40L levels are elevated in hypertensive patients and might discriminate hypertensive patients at a high risk of cardiovascular events. This review will summarize the present understanding of the contribution of sCD40L to inflammation, thrombosis and neoangiogenesis in hypertension. Furthermore, given the well established effects that antihypertensive drugs exert on the vasculature beyond blood pressure lowering (pleiotropic effects), we will also discuss the effects of antihypertensive treatment on these phenomena.