Cardioplegia is fundamental to the surgical repair of congenital heart defects by protecting the heart against ischaemia/reperfusion injury, characterised by low cardiac output and troponin release in the early postoperative period. The immature myocardium exhibits structural, physiological and metabolic differences from the adult heart, with a greater sensitivity to calcium overload-mediated injury during reperfusion. Del Nido cardioplegia was designed specifically to protect the immature heart, is widely used in North America and may provide better myocardial protection in children; however, it has not been commercially available in the UK, where most centres use St Thomas' blood cardioplegia. There are no phase 3 clinical trials in children to support one solution over another and this lack of evidence, combined with variations in practice, suggests the presence of clinical equipoise. The best cardioplegia solution for use in children, and the impact of age and other clinical factors remain unknown. In this Hunterian lecture, I propose an evidence-based strategy to improve myocardial protection during cardiac surgery in children through: (1) conducting multicentre clinical trials of established techniques; (2) improving our knowledge of ischaemia/reperfusion injury in the setting of cardioplegic arrest; (3) applying this to drive innovation, moving beyond current cardioplegia solutions; (4) empowering personalised medicine, through combining clinical and genomic data, including ethnic diversity; and (5) understanding the impact of cardioplegic arrest on the late outcomes that matter to patients and their families.