The recent report of DCM phenotype in Rgs2−/− and Rgs5−/− mice raises the question whether environmental factors and lifestyles (including the increasing popularity and use of recreational drugs such as methamphetamine and fentanyl) could potentially impinge on the expression or function of cardiac RGS proteins, thereby increasing the risk of DCM in individuals harboring disease gene variants (Fig. 1). This evidence concerns the gene PITX2 and familial dilated cardiomyopathy.