The HAND basic Helix-Loop-Helix (bHLH) transcription factors are essential for normal cardiac and extraembryonic development. Although highly evolutionarily conserved genes, HAND cardiac expression patterns differ across species. Mouse expression of HAND1 and HAND2 was reported absent in the adult heart. Human HAND genes are expressed in the adult heart and HAND1 expression is downregulated in cardiomyopathies. As rodent and human expression profiles are inconsistent, we re-examined expression of HAND1 and HAND2 in adult-rodent hearts. HAND1 and HAND2 are expressed in adult-rodent hearts and HAND2 is expressed in the atria. Induction of cardiac hypertrophy shows modulation of HAND expression, corresponding with observations in human cardiomyopathy. The downregulation of HAND expression observed in rodent hypertrophy and human cardiomyopathy may reflect a permissive role allowing, cardiomyocytes to reinitiate the fetal gene program and initiate the adaptive physiological changes that allow the heart to compensate (hypertrophy) for the increase in afterload.