Nitric oxide (NO) plays a crucial role in many aspects of the pathophysiology of heart failure. NO is a double-edged sword; NO inhibits ischemia/reperfusion (I/R) injury, represses inflammation, and prevents left ventricular (LV) remodeling, whereas excess NO and co-existence of reactive oxygen species (ROS) with NO are injurious. The failing heart is exposed to not only oxidative stress by a plethora of humoral factors and inflammatory cells but also nitrosative stress. Activation of nitric oxide synthase (NOS) of any isoforms, [i.e., endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS)], concomitant with oxidative stress results in NOS uncoupling, leading to further oxidative/nitrosative stress. Indiscriminate removal of oxidative stress is not an effective means to prevent this detrimental process, because oxidative stress is necessary for an adaptive mechanism for cell survival against noxious stimuli. Therefore, removal of ROS in a site-specific manner or inhibition of the source of injurious ROS without affecting redox-sensitive survival signal transduction pathways represents a promising approach to elicit the beneficial effect of NO. Recent emerging pharmacological tools and regular exercise inhibit ROS generation in the proximity of NOSs, thereby increasing bioavailable NO and exerting cardioprotection against I/R injury and LV remodeling.