Cardiac remodeling occurs as an adaptive response to chronic increases in hemodynamic load and neurohormonal stimulation but may become maladaptive over time, leading to deleterious structural and functional alterations and manifesting clinically as congestive heart failure. On a cellular level, cardiac myocyte hypertrophy and apoptosis, fibroblast proliferation, and changes in the extracellular matrix are some of the principal alterations underlying the remodeling process. In recent years, nitric oxide (NO) has been recognized to modulate contractile function, myocardial oxygen metabolism, ventricular hypertrophy and apoptosis, and fibrosis. The identification of the different isoforms of NO synthase and the generation of genetically modified mice lacking or overexpressing these enzymes have provided new insights into the complexity of NO biology and its multifaceted role in cardiac remodeling and heart failure.