Although the net balance between vasoconstriction and vasodilation determines the tone of the blood vessel, the vasodilatory-vasoconstrictive response following a challenge may also be determined by the intrinsic mechanical and biological properties of the vascular smooth muscle. This article reviews the action of nitric oxide, acetylcholine,and insulin; the effects of hyperglycemia, increase in free fatty acids, diabetes, and obesity on the vasculature; treatment of hypertension in diabetes; the benefits of lowering blood pressure and intensity of blood pressure control; and compares specific antihypertensive therapies on cardiovascular outcomes. The effects of antihypertensive therapy on microvascular complications, choice of antihypertensive regimen, antioxidant and anti-inflammatory effects of antihypertensive drugs, and the potential role of antidiabetic drugs in the treatment of hypertension are also presented.