During the processes leading to adverse cardiac remodeling and heart failure, cardiomyocytes react to neurohumoral stimuli and biomechanical stress by activating pathways that induce pathological hypertrophy. The gene expression patterns and molecular changes observed during cardiac hypertrophic remodeling bare resemblance to those observed during fetal cardiac development. The re-activation of fetal genes in the adult failing heart is a complex biological process that involves transcriptional, posttranscriptional and epigenetic regulation of the cardiac genome. In this review, the mechanistic actions of transcription factors, microRNAs and chromatin remodeling processes in regulating fetal gene expression in heart failure are discussed.