Adaptation of the heart to intrinsic and external stress involves complex modifications at the molecular and cellular level that lead to tissue remodeling and functional compensation or failure depending upon the nature, intensity and chronicity of the stress. Signaling mechanisms mediated by reactive oxygen species (ROS) are now known to play important roles in many aspects of this complex process. In particular, the tightly regulated generation of ROS by NADPH oxidases appears especially important in key signaling events that drive the development of cardiomyocyte hypertrophy, fibrosis, extracellular matrix remodelling and cell apoptosis. This review discusses the signaling pathways modulated by ROS during the development of cardiac remodelling and failure with a particular emphasis on the role of NADPH oxidases.