Signal transduction through G-protein-coupled receptors (GPCRs) is central for the regulation of virtually all cellular functions and has been widely implicated in human disease. Regulators of G-protein signaling (RGS proteins) belong to a diverse protein family that was originally discovered for their ability to accelerate signal termination in response to GPCR stimulation, thereby reducing the amplitude and duration of GPCR effects. All RGS proteins share a common RGS domain that interacts with G protein α subunits and mediates their biological regulation of GPCR signaling. However, RGS proteins differ widely in size and the organization of their sequences flanking the RGS domain, which contain several additional functional domains that facilitate protein-protein (or protein-lipid) interactions. RGS proteins are subject to posttranslational modifications, and, in addition, their expression, activity, and subcellular localization can be dynamically regulated. Thus, there exists a wide array of mechanisms that facilitate their proper function as modulators and integrators of G-protein signaling. Several RGS proteins have been implicated in the cardiac remodeling response and heart rate regulation, and changes in RGS protein expression and/or function are believed to participate in the pathophysiology of cardiac hypertrophy, failure and arrhythmias as well as hypertension. This review is based on recent advances in our understanding of the expression pattern, regulation, and functional role of canonical RGS proteins, with a special focus on the healthy heart and the diseased heart. In addition, we discuss their potential and promise as therapeutic targets as well as strategies to modulate their expression and function.