Evidence obtained in multiple experimental models has revealed that cardiac 'conditioning' strategies--including ischaemic preconditioning, postconditioning, remote conditioning and administration of pharmacological conditioning mimetics--are profoundly protective and significantly attenuate myocardial ischaemia-reperfusion injury. As a result, there is considerable interest in translating these cardioprotective paradigms from the laboratory to patients. However, the majority of studies investigating conditioning-induced cardioprotection have utilized healthy adult animals devoid of the risk factors and co-morbidities associated with cardiovascular disease and acute myocardial infarction. The aim of this article is to summarize the growing consensus that two well established risk factors, aging and diabetes mellitus, may render the heart refractory to the favourable effects of myocardial conditioning, and discuss the clinical implications of a loss in efficacy of cardiac conditioning paradigms in these patient populations.