G protein-coupled receptors (GPCRs) play pivotal roles in regulation of cardiovascular homeostasis across all vertebrate species, including humans. In terms of normal cellular function, termination of GPCR signaling via the heterotrimeric G proteins is equally (if not more) important to its stimulation. The Regulator of G protein Signaling (RGS) protein superfamily are indispensable for GPCR signaling cessation at the cell membrane, and thus, for cellular control of GPCR signaling and function. Perturbations in both activation and termination of G protein signaling underlie many examples of cardiovascular dysfunction and heart disease pathogenesis. Despite the plethora of over 30 members comprising the mammalian RGS protein superfamily, each member interacts with a specific set of second messenger pathways and GPCR types/subtypes in a tissue/cell type-specific manner. An increasing number of studies over the past two decades have provided compelling evidence for the involvement of various RGS proteins in physiological regulation of cardiovascular GPCRs and, consequently, also in the pathophysiology of several cardiovascular ailments. This chapter summarizes the current understanding of the functional roles of RGS proteins as they pertain to cardiovascular, i.e., heart, blood vessel, and platelet GPCR function, with a particular focus on their implications for chronic heart failure pathophysiology and therapy.