Translation of cardioprotective interventions aimed at reducing myocardial injury during ischaemia–reperfusion from experimental studies to clinical practice is an important yet unmet need in cardiovascular medicine. One particular challenge facing translation is the existence of demographic and clinical factors that influence the pathophysiology of ischaemia–reperfusion injury of the heart and the effects of treatments aimed at preventing it. Among these factors, age and sex are prominent and have a recognised role in the susceptibility and outcome of ischaemic heart disease. Remarkably, some of the most powerful cardioprotective strategies proven to be effective in young animals become ineffective during ageing. This article reviews the mechanisms and implications of the modulatory effects of ageing and sex on myocardial ischaemia–reperfusion injury and their potential effects on cardioprotective interventions.LINKED ARTICLESThis article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc