Acids and their conjugate bases accumulate in or dissipate from the interstitial space when tissue perfusion does not match the metabolic demand. Extracellular acidosis dilates most arterial beds, but associated acid-base disturbances-e.g., intracellular acidification and decreases in HCO concentration-can also elicit pro-contractile influences that diminish vasodilation and even dominate in some vascular beds to cause vasoconstriction. The ensemble activities of the acid-base-sensitive reactions in vascular smooth muscle and endothelial cells optimize vascular resistance for blood pressure control and direct the perfusion towards active tissue. In this review, we describe the mechanisms of intracellular pH regulation in the vascular wall and discuss how vascular smooth muscle and endothelial cells sense acid-base disturbances. We further deliberate on the functional effects of local acid-base disturbances and their integrated cardiovascular consequences under physiological and pathophysiological conditions. Finally, we address how mutations and polymorphisms in the molecular machinery that regulates pH locally and senses acid-base disturbances in the vascular wall can result in cardiovascular disease. Based on the emerging molecular insight, we propose that targeting local pH-dependent effectors-rather than systemic acid-base disturbances-has therapeutic potential to interfere with the progression and reduce the severity of cardiovascular disease.