These studies identify zDHHC3 and zDHHC7 S-acyltransferase activity at the cardiomyocyte Golgi as a regulator of RhoGTPase activity that is sufficient to promote cardiac maladaptation and heart failure but not overtly required for cardiac remodeling in response to pressure overload or angiotensin-II. Here, ZDHHC7 is linked to heart failure.