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. •We describe three distinct levels of fetal gene regulation in the diseased heart.•We focus on transcriptional mechanisms and epigenetic gene switches.•Epigenetic mechanisms are subdivided in chromatin remodeling enzymes and non-coding RNA mechanisms.•We conclude that all distinct mechanisms are closely intertwined and co-regulated.•More detailed knowledge will identify future sites for therapeutic intervention.