Cardiac mitochondrial metabolism can be manipulated by: (i) addition of metabolites or cofactors; (ii) activation of enzymes or complexes involving generation of reduced equivalents; (iii) control of synthesis of mitochondrial factors or mitochondrial biogenesis. The most effective means of stimulating ATP synthesis when the heart is exposed to high workloads or inotropic agents is through elevation of mitochondrial Ca2+ concentrations. Physiologically, this occurs through an increase in electron transport-limiting components or NADH supply via stimulation of Ca2+-dependent mitochondrial dehydrogenases. Drugs such as ubiquinone, diltiazem, and trimetazidine seem to be effective in achieving this goal. Drugs that reduce oxidative damage and mitochondrial DNA mutations, or genetic manipulations that improve mitochondrial biogenesis, can be considered additional interventions improving cardiac mitochondrial function...