<p>A central paradigm in cardiac biology is the reactivation of the fetal gene programme in the adult heart in response to stress. This so-called ‘fetal gene hypothesis’ was first proposed almost 40 years ago following the observation that certain fetal contractile protein isoforms were re-expressed in hypertrophied ventricles in the rodent heart in response to haemodynamic overload. Consequently, this concept was broadly adopted, and activation of the fetal gene programme became synonymous in the literature with the cardiac stress response. Transcriptomic and epigenomic profiling studies from the past 20 years have revealed the extent to which the diseased heart redeploys fetal gene programmes in response to stress. In this Review, we describe the historical origins of the fetal gene hypothesis and re-evaluate the general principles of fetal gene regulation in heart development, disease and regeneration.</p>