Reactive oxygen species (ROS) and the cellular thiol redox state are crucial mediators of multiple processes in cells like growth, differentiation and apoptosis. Excessive ROS production or oxidative stress is associated with several diseases, including cardiovascular disorders like ischemia/reperfusion. To prevent ROS-induced disorders, the heart is equipped with effective antioxidant systems. Key players in defence against oxidative stress are members of the thioredoxin fold family of proteins. Of these, thioredoxins and glutaredoxins maintain a reduced intracellular redox state in mammalian cells by the reduction of protein thiols. The reversible oxidation of CGPC or CP(S)YC active site cysteine residues is used in reversible electron transport. Thioredoxins and glutaredoxins belong to corresponding systems consisting of NADPH, thioredoxin reductase and thioredoxin or NADPH, glutathione reductase, glutathione and glutaredoxin, respectively. Thioredoxin as well as glutaredoxin activities appear to be very important for progression and severity of several cardiovascular disorders. These proteins function not only as antioxidants, they inhibit or activate apoptotic signaling molecules like apoptosis signal-regulating kinase 1 (ASK-1) and Ras or transcription factors like NF-B. Thioredoxin activity is regulated by the endogenous inhibitor thioredoxin binding protein 2 (TBP2) indicating an important role of the balance between thioredoxin and TBP2 levels in cardiovascular diseases. In this review, we will summarize cardioprotective effects of endogenous thioredoxin and glutaredoxin systems as well as the high potential in clinical applications of exogenously applied thioredoxin or glutaredoxin or the induction of endogenous thioredoxin and glutaredoxin systems.