Although a major contribution to cardiac diseases is suggested to be provided by formation of reactive oxygen species (ROS) within mitochondria, sites and mechanisms are matters of debate. Respiratory chain is generally indicated as a main site for ROS formation. However, other mitochondrial components are likely to contribute to ROS generation. Recent reports highlight the relevance of monoamine oxidases (MAO). The importance of these enzymes in the irreversibility of ischemic heart injury will be discussed along with the cardioprotective effects elicited by MAO inhibition and knockout, also in relation to the involvement of the mitochondrial permeability transition pore. In addition the discussion will address the following points: (i) mechanisms linking oxidative stress to altered mitochondrial dynamics; (ii) oxidation of myofibrillar proteins as a major consequence of oxidative stress generated by mitochondria (iii) the relevance of mitochondrial ROS generation in contractile alterations of cardiac myocytes in a wide array of conditions, such as pressure overload, doxorubicin toxicity, diabetic cardiomyopathy, that are largely ameliorated by MAO inhibition; (iv) the contribution of MAO in experimental models of muscular dystrophy and the beneficial effects of MAO inhibition that suggest a novel therapeutic approach for these devastating diseases.