The human heart can increase in size in two diverse settings. “Physiological” cardiac hypertrophy occurs in well-trained athletes and enhances heart function, whereas “pathological” hypertrophy occurs in response to heart attacks or hypertension and compromises heart function. To identify molecular factors that promote beneficial hypertrophy, Riquelme et al. studied Burmese pythons, which show a dramatic 40% increase in heart mass within 2 to 3 days after consumption of a large meal. This extreme physiological response was promoted by specific fatty acids in postprandial python plasma. In vitro and in vivo administration of these fatty acids stimulated signaling pathways associated with physiological hypertrophy in both python and mouse cardiac myocytes. Therapeutic interventions based on these fatty acids could potentially provide a way to enhance the heart’s performance in patients.