Adult cardiomyocytes are terminal cells with minimal replicative potential. This leads to the inevitable deterioration of cardiac function once functional reserve ceases to compensate for lost contractile tissue. It follows that preservation of structure and function is the ultimate target of every therapeutic intervention. In this endeavor the cardiomyocyte has a number of friends on hand: they include stalwarts such as oxygen, calcium, and mitochondrial energy substrates (free fatty acids, carbohydrates, and glucose), but also a more recently discovered pacemaker component, the If current. Having identified the multiple friends available, the therapist must harness the services of each, while at the same time keeping a watchful eye for the cardiomyocyte’s foes. Under non-physiological conditions—primarily ischemia—erstwhile firmest friends mutate into the most formidable of foes: oxygen readmitted into ischemic tissue may no longer be used by mitochondria to drive oxidative phosphorylation, but instead converted into lethal oxygen free radicals, while mitochondria, by admitting calcium through the megapore, play a pivotal role in determining programmed cell death. Treatment is a fine balance between maximizing the potential of friends and minimizing the potential of foes...