Brief periods of ischaemia increase the myocardial resistance against a subsequent and more severe ischaemia. In this “ischaemic pre-conditioning” (IPC), articulated in two phases, a pivotal mechanism resides in the activation of cardiac mitochondrial ATP-sensitive potassium channels (mitoK_ATP). Therefore, mitoK_ATP-openers can mimic the IPC and can induce a “pharmacological pre-conditioning” against the myocardial damage due to ischaemic episodes. In particular, those molecules endowed of selectivity towards the mitoK_ATP channels have been proposed as anti-ischaemic cardioprotective drugs, devoid of other significant side-effects (such as negative inotropic activity, hypotension or hyperglycemia) linked to the opening of sarcolemmal K_ATP channels. In this paper, the experimental observation accounting for the relevant role of mitoK_ATP channels in IPC, the mechanisms involved and some representative molecules acting as mitoK_ATP-activators are reported.