Essential hypertension (EH) results when the balance between vasoconstriction and vasodilation is shifted in favor of vasoconstriction. This balance is controlled by the interaction of genetic and epigenetic factors. When there is an unstable balance, vitamin D deficiency as an epigenetic factor triggers a shift to the side of vasoconstriction. In this article, we critically analyze clinical findings on the effect of vitamin D on blood pressure, combined with progress in molecular mechanisms. We find that vitamin D repletion exerts a clinically significant antihypertensive effect in vitamin D-deficient EH patients. Of note, a few trials reported no antihypertensive effect from vitamin D due to suboptimal study design. Short-term vitamin D supplementation has no effect on blood pressure in normotensive subjects. This could explain the mixed results and may provide a theoretical basis for future trials to identify beneficial effects of vitamin D in intervention for EH.