The opioid receptor family, with associated endogenous ligands, has numerous roles throughout the body. Moreover, the delta opioid receptor (DORs) has various integrated roles within the physiological systems, including the cardiovascular system. While DORs are important modulators of cardiovascular autonomic balance, they are well-established contributors to cardioprotective mechanisms. Both endogenous and exogenous opioids acting upon DORs have roles in myocardial hibernation and protection against ischaemia-reperfusion (I-R) injury. Downstream signalling mechanisms governing protective responses alternate, depending on the timing and duration of DOR activation. The following review describes models and mechanisms of DOR-mediated cardioprotection, the impact of co-morbidities and challenges for clinical translation.