RGS family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G_αsubunits of heterotrimeric G proteins. RGS proteins are able to deactivate G protein subunits of the G_iα, G_oαand G_qαsubtypes when testedin vitroandin vivo. Although the function of RGS proteins in cardiac physiology is unknown, their ability to deactivate G_αsubunits suggests that they may inhibit the action of muscarinic, α-adrenergic, endothelin, and other agonists. To evaluate the role of RGS family members in the regulation of cardiac physiology, we investigated the expression pattern of two RGS genes in normal and diseased rat heart tissue. RGS3 and RGS4 mRNAs and proteins were detected in adult myocardium. RGS3 and RGS4 gene expression was markedly enhanced in two model systems of cardiac hypertrophy: growth factor-stimulated cultured neonatal rat cardiomyocytes and pulmonary artery-banded (PAB) mice. RGS3 and RGS4 mRNA levels were reduced in failing myocardium obtained from SHHF/Mcc-fa^cp(SHHF) rats. These findings support the hypothesis that RGS gene expression is highly regulated in myocardium and imply that RGS family members play an important role in the regulation of cardiac function.