Atherosclerosis leads to narrowing of vessels and acute coronary syndrome resulting in ischemic events due to either vasospasm or decreased blood flow. Atherosclerosis and acute coronary syndrome are more common in diabetes mellitus. Hyperglycemia and hypercholesterolemia in diabetes predispose the arteries to plaque development. Smoking, hypertension, male sex, and family history or genetic susceptibility are other predisposing factors for plaque development. Depending on the size, morphology, and symptoms of the patients, plaques can be classified as stable and unstable plaques. Unstable plaques are characterized by the presence of thin fibrous cap, necrotic core, and proliferation of vascular smooth muscle cells, angiogenesis and calcification. Plaque formation initiates with fatty streak and progresses through atheroma, atheromatous plaque to fibroatheromatous plaque. Fibroatheromatous plaques with thick fibrous cap are stable plaques. Thinning of the fibrous cap makes a plaque unstable, prone to rupture and thrombus formation. Mechanisms such as increased inflammation, foam cell deposition, impaired repair mechanism, endothelial cell dysfunction, vascular smooth muscle cell proliferation, angiogenesis, intra-plaque hemorrhage, and calcification which facilitate the plaque rupture are increased in diabetes mellitus. Thus, diabetes mellitus increases the prevalence of plaque formation and rupture. Diabetes mellitus affects various cellular and molecular effectors involved in plaque development and rupture. Understanding these cellular and molecular effectors and involved mechanisms in association with diabetes mellitus is essential for the development of potential therapeutic strategies. This review is a critical overview on the effect of hyperglycemia in diabetes mellitus on the pathogenesis of plaque formation and rupture.