Significance: Reactive oxygen species (ROS) play a key role in the pathogenesis of cardiac remodeling and the subsequent progression to heart failure (HF). Nicotinamide adenosine dinucleotide phosphate (NADPH) oxidases (NOXs) are one of the major sources of ROS and are expressed in different heart cell types, including cardiomyocytes, endothelial cells, fibroblasts, and inflammatory cells. Recent Advances: NOX-derived ROS are usually produced in a regulated and spatially confined fashion and typically linked to specific signaling. The two main cardiac isoforms, namely nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) and nicotinamide adenine dinucleotide phosphate oxidase isoform 4 (NOX4), possess different biochemical and (patho)physiological properties and exert distinct effects on the cardiac phenotype in many settings. Recent work has defined important cell-specific effects of NOX2 that contribute to pathological cardiac remodeling and dysfunction. NOX4, on the other hand, may exert protective effects by stimulating adaptive stress responses, with recent data showing that NOX4-mediated signaling regulates transcription and metabolism in the heart. Critical Issues: The inhibition of NOX2 appears to be a very promising therapeutic target to ameliorate pathological cardiac remodeling. If the beneficial effects of NOX4 can be enhanced, this might be a unique approach to boosting adaptive responses and thereby impact cell survival, activation, contractility, and growth. Future Directions: Increasing knowledge regarding the intricacies of NOX-mediated signaling may yield tractable therapeutic targets, in contrast to the non-specific targeting of oxidative stress. Antioxid. Redox Signal. 38, 371-387.