The present invention provides screening methods for identifying agents that modulate the activity of mitochondrial aldehyde dehydrogenase-2 (AldDH2), as well as agents identified by the screening methods. The present invention further provides methods of reducing ischemic tissue damage or free-radical induced damage in an organ, the methods generally involving contacting the organ with an agent that increases AldDH2 levels and/or activity. The present invention further provides methods of treating solid tumors, the methods generally involving administering an agent that decreases AldDH2 levels and/or activity.