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Increased vascular calcification and stiffness is associated with aging and accelerated in patients with atherosclerosis, diabetes mellitus and end stage renal disease, which increases risk of cardiovascular events and mortality. We and others have demonstrated an integral role of the osteogenic transcription factor Runx2 in promoting vascular calcification and stiffness. Our recent studies uncovered a novel role of vascular smooth muscle cell-derived Runx2 in regulating aortic aneurysm and cerebral vascular function. Mechanistic studies have elucidated a causative link between oxidative stress and vascular protein O-linked GlcNAc modification and vascular Runx2 upregulation, vascular calcification and stiffness; and further highlighted a beneficial effect of dietary potassium in mitigating Runx2 upregulation and vascular calcification. The identified novel mechanisms linking oxidative stress and glucose metabolism to vascular Runx2 upregulation and vascular dysfunction may shed lights on therapeutic targets for preventing and/or inhibiting vascular calcification and stiffness in cardiovascular disease and aging.