This review provides an overview of the molecular mechanisms underlying DCM, with a focus on the current understanding of changes in G protein signaling regulation by regulator of G protein signaling (RGS) proteins and related regulatory proteins in cardiomyocytes, vascular cells, and fibroblasts, as relates to DCM pathogenesis and progression to heart failure. Here, PITX2 is linked to familial dilated cardiomyopathy.