Coronary artery disease (CAD) is a leading cause of death, and its genetic mechanism has been always a major research concern. Recently, increasing evidence has indicated that the aldehyde dehydrogenase 2 (ALDH2) polymorphism, known as Glu504Lys (rs671), may contribute to CAD development. ALDH2 has been well known as a key enzyme in alcohol metabolism, and subjects with *504Lys allele exist in 30-50% of the East Asian population (6% of the world's population). However, recent studies have indicated that the *504Lys allele of the ALDH2 gene may be associated with the pathogenesis of CAD in a given number of Chinese, Japanese, and Korean people. This discovery has been further confirmed by a genome-wide association study in 2012 that identified the link of ALDH2 Glu504Lys polymorphism to CAD susceptibility. ALDH2 may therefore serve as an important target for CAD intervention. Several studies have suggested that ALDH2 polymorphism plays an important role in the progress of CAD through multiple mechanisms, including the regulation of alcohol consumption, inflammation, endothelial progenitor cells, oxidative stress, asymmetric dimethylarginine, endothelial nitric oxide synthase, and other CAD-promoting factors. Furthermore, the ALDH2 Glu504Lys polymorphism has been shown to be associated with certain traditional cardiovascular risk factors, such as dyslipidemia, hypertension, and diabetes mellitus or hyperglycemia. In this review, we update the current research on the association of the Glu504Lys polymorphism with the susceptibility to CAD. We also highlight and discuss the underlying mechanisms, by which the ALDH2 Glu504Lys polymorphism may be targeted for the prevention and treatment of CAD.