Early coronary artery reperfusion improves outcomes for patients with ST-segment elevation myocardial infarction (STEMI), but morbidity and mortality after STEMI remain unacceptably high. The primary deficits seen in these patients include inadequate pump function, owing to rapid infarction of muscle in the first few hours of treatment, and adverse remodelling of the heart in the months that follow. Given that attempts to further reduce myocardial infarct size beyond early reperfusion in clinical trials have so far been disappointing, effective therapies are still needed to protect the reperfused myocardium. In this Review, we discuss several approaches to preserving the reperfused heart, such as therapies that target the mechanisms involved in mitochondrial bioenergetics, pyroptosis, and autophagy, as well as treatments that harness the cardioprotective properties of inhaled anaesthetic agents. We also discuss potential therapies focused on correcting the no-reflow phenomenon and its effect on healing and adverse left ventricular remodelling.