The E3 ubiquitin ligases, MuRF1 and MAFbx, are selectively expressed in striated muscle, and are implicated in the regulation of both skeletal and cardiac muscle mass through mechanisms that are still being determined, but are thought to involve the targeting of specific proteins through poly‐ubiquitylation for degradation by the ubiquitin proteasome system. Studies on mice with a null deletion of either MuRF1 or MAFbx reveal no cardiac phenotype in young unchallenged mice of either knock out (KO) line. In this study, we examined the hearts of MuRF1 and MAFbx KO mice up to the age of 18 months, and found that MAFbx KO mice develop congestive heart failure and die prematurely between the ages of 16–18 months. In contrast, MuRF1 mice age normally and exhibit only a mild physiological enlargement of the heart. At 18m MAFbx KO mice have significant increases in heart and lung wet weights. Histological evaluation of mice at 18m revealed enlarged atria and ventricle, as well as, increased fibrosis in MAFbx KO compared to WT and MuRF1 KO mice. Further, MAFbx KO mice displayed a significant reduction in cardiac function relative to age‐matched WT mice as measured by a decrease in percentage of fractional shortening and left ventricle ejection fraction. This study demonstrates a significant divergence in the physiology of mice with deletions in either MuRF1 or MAFbx. Funding was provided by the Muscular Dystrophy Association.