Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. Repression of anti-hypertrophic pathways has not been demonstrated to cause cardiac hypertrophy in vivo. Hop is an unusual homeodomain protein that is expressed by embryonic and postnatal cardiac myocytes. Unlike other homeodomain proteins, Hop does not bind to DNA. Rather, it modulates cardiac growth and proliferation by inhibiting the transcriptional activity of serum response factor (SRF) in cardiomyocytes. Here we show that Hop can inhibit SRF-dependent transcriptional activation by recruiting histone deacetylase (HDAC) activity and can form a complex that includes HDAC2, one of the class I HDACs. Transgenic mice that over-express Hop develop severe cardiac hypertrophy by 4 weeks of age and progress with cardiac fibrosis and premature death. A mutant form of Hop, which is unable to repress transcription or to recruit HDAC activity, does not induce hypertrophy. Furthermore, treatment of Hop transgenic mice with trichostatin A and valproic acid, chemical HDAC inhibitors, greatly attenuates cardiac hypertrophy. In addition, trichostatin A also attenuates hypertrophy induced by infusion of isoproterenol. These results suggest that chromatin remodeling and repression of otherwise active transcriptional processes can result in hypertrophy and heart failure, and this process can be blocked with chemical HDAC inhibitors.