Cardiomyocyte apoptosis plays a mechanistic role in murine heart failure models. Cardiac-restricted expression of a conditional caspase-8 transgene indicates that low, but abnormal, levels of cardiomyocyte apoptosis (0.023% vs. 0.002% in controls) are sufficient to cause a lethal dilated cardiomyopathy. Similarly, cardiac-specific expression of Gαq induces the transcriptional activation of the BH3-only–like protein Nix, which results in cardiomyocyte apoptosis and dilated cardiomyopathy. The latter is severely exacerbated and lethal during pregnancy. Caspase inhibitors or expression of sNix, an antiapoptotic Nix splice variant, ameliorate cardiomyopathy in these models. In addition, caspase inhibition and sNix decrease mortality in the Gαq peripartum cardiomyopathy model.