Aldehyde dehydrogenase 2 (ALDH2) is best known for its critical detoxifying role in liver alcohol metabolism. However, ALDH2 dysfunction is also involved in a wide range of human pathophysiological situations and is associated with complications such as cardiovascular diseases, diabetes mellitus, neurodegenerative diseases and aging. A growing body of research has shown that ALDH2 provides important protection against oxidative stress and the subsequent loading of toxic aldehydes such as 4-hydroxy-2-nonenal and adducts that occur in human diseases, including ischemia reperfusion injury (IRI). There is increasing evidence of its role in IRI pathophysiology in organs such as heart, brain, small intestine and kidney; however, surprisingly few studies have been carried out in the liver, where ALDH2 is found in abundance. This study reviews the role of ALDH2 in modulating the pathways involved in the pathophysiology of IRI associated with oxidative stress, autophagy and apoptosis. Special emphasis is placed on the role of ALDH2 in different organs, on therapeutic "preconditioning" strategies, and on the use of ALDH2 agonists such as Alda-1, which may become a useful therapeutic tool for preventing the deleterious effects of IRI in organ transplantation.