Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide. For a large number of patients with CHD, coronary artery bypass graft (CABG) surgery remains the preferred strategy for coronary revascularization. Over the last 10 years, the number of high-risk patients undergoing CABG surgery has increased significantly, resulting in worse clinical outcomes in this patient group. This appears to be related to the ageing population, increased co-morbidities (such as diabetes, obesity, hypertension, stroke), concomitant valve disease, and advances in percutaneous coronary intervention which have resulted in patients with more complex coronary artery disease undergoing surgery. These high-risk patients are more susceptible to peri-operative myocardial injury and infarction (PMI), a major cause of which is acute global ischaemia/reperfusion injury arising from inadequate myocardial protection during CABG surgery. Therefore, novel therapeutic strategies are required to protect the heart in this high-risk patient group. In this article, we review the aetiology of PMI during CABG surgery, its diagnosis and clinical significance, and the endogenous and pharmacological therapeutic strategies available for preventing it. By improving cardioprotection during CABG surgery, we may be able to reduce PMI, preserve left ventricular systolic function, and reduce morbidity and mortality in these high-risk patients with CHD.