Thioredoxin (Trx) is an important antioxidant cellular system that playsan important role in cardioprotection against ischemia/reperfusion injury. Thecardioprotective effects include a reduction of infarct size and anamelioration of ventricular and mitochondrial dysfunction that occurs inmyocardial stunning. Particularly, Trx1 plays a protective role against theoxidative stress caused by an increase of reactive oxygen speciesconcentration, as occurs during the reperfusion after an ischemic episode, andalso could activate proteins related to pro-survival pathways such asMAP-kinases, Akt and GSK3b. It has been also shown that, at least partially,Trx-1 takes part of cardioprotective mechanisms such as ischemicpreconditioning (PC) and postconditioning (PostC). However, comorbidities suchas aging can modify this powerful cellular defense, leading to decreasecardioprotection, and even ischemic PC and PostC induced in aged animal modelsfailed to decrease infarct size. Therefore, the lack of success of antioxidantstherapies to treat ischemic heart disease could be solved avoiding the damageof Trx system.