Adaptation of the heart to intrinsic and external stress involves complex modifications at the molecular and cellular levels that lead to tissue remodeling, functional and metabolic alterations, and finally to failure depending upon the nature, intensity, and chronicity of the stress. Reactive oxygen species (ROS) have long been considered as merely harmful entities, but their role as second messengers has gradually emerged. At the same time, our comprehension of the multifaceted role of nitric oxide (NO) and the related reactive nitrogen species (RNS) has been upgraded. The tight interlay between ROS and RNS suggests that their imbalance may implicate the impairment in physiological NO/redox-based signaling that contributes to the failing of the cardiovascular system. This review initially provides basic concepts on the role of nitroso/oxidative stress in the pathophysiology of heart failure with a particular focus on sources of ROS/RNS, their downstream targets, and endogenous modulators. Then, the role of NO/redox regulation of cardiomyocyte function, including calcium homeostasis, electrogenesis, and insulin signaling pathways, is described. Finally, an overview of old and emerging therapeutic opportunities in heart failure is presented, focusing on modulation of NO/redox mechanisms and discussing benefits and limitations. Antioxid. Redox Signal. 14, 289–331.