In this review, a rationale is presented for how hypercholesterolemia, hypertension, diabetes mellitus, end-stage renal disease, renal dialysis, and prolonged stress can all lead to atherosclerosis, ischemic heart disease, and stroke. The data indicate that Mg deficiency caused either by poor diet and/or errors in Mg metabolism may be a missing link between diverse cardiovascular risk factors and atherosclerosis. Data from our laboratories and others indicate that reduction in extracellular and intracellular free Mg ions (Mg2+) can induce an entire array of pathophysiological phenomena known to be important in atherogenesis, that is, vasospasm, increased vascular reactivity, elevation in [Ca2+]i, formation of proinflammatory agents, oxygen radicals, platelet aggegation, reduction in cardiac bioenergetics, cardiac failure, oxidation of lipoproteins, gender-related modulation of endothelial-derived relaxing factor/NO, changes in membrane fatty acid saturation, changes in membrane plasmalogens and N-phospholipids (suggesting changes in intracellular phospholipid signals), and probably transcription factors.