Cellular stress, notably oxidative, inflammatory and endoplasmic reticulum (ER) stress is implicated in the pathogenesis of cardiovascular disease. Modifiable risk factors for cardiovascular disease such as diabetes, hypercholesterolemia, saturated fat consumption, hypertension and cigarette smoking cause ER stress while currently known cardioprotective drugs with diverse pharmacodynamics share a common pleiotropic effect of reducing ER stress. Selective targeting of oxidative stress with known antioxidative vitamins has been ineffective in reducing cardiovascular risk. This "antioxidant paradox" is partially attributed to the unexpected aggravation of ER stress by the antioxidative agents used. In contrast, some of the contemporary anti-hyperglycemic drugs inhibit both oxidative stress and ER stress in human coronary artery endothelial cells. Unlike sulfonylureas, meglitinides, α glucosidase inhibitors and thiazolidinediones, metformin, glucagon like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors are the only anti-hyperglycemic drugs that reduce ER stress caused by pharmacological agents (tunicamycin) or hyperglycemic conditions. Clinical trials with selective ER stress modifiers are needed to test the suitability of ER stress as a therapeutic target for cardiovascular disease.