Reactive oxygen species and reactive nitrogen species are produced endogenously by cardiomyocytes and are fundamental signaling molecules that regulate cellular function. Production of ROS and RNS is finely tuned to maintain proper myocardial function, but is altered in many pathophysiological conditions, therefore contributing to worsening myocardial dysfunction and ultimately heart failure. Indeed, an excess of ROS and RNS is central in many pathways leading to cardiac hypertrophy and failure, and the correct regulation of the nitroso-redox balance is fundamental for the function of the main components of the EC-coupling machinery. Broad antioxidant therapies have been proposed to improve myocardial function, but these therapies blunt even physiological ROS and RNS signaling, bringing limited, if any, beneficial effect. On the other hand, more targeted interventions on specific sources or pathways may produce promising results.