© 2014, Springer Science+Business Media New York. The incidence of obesity with insulin resistance is increasing worldwide. This condition is also known as a risk factor of coronary artery disease and associated with increased arrhythmias, impaired left ventricular function, and increased infarct size during cardiac ischemia-reperfusion (I/R) injury. The proposed mechanisms are due to impaired glucose utilization and pro-survival signaling molecules, and increased inflammatory cytokines, which have been demonstrated in the I/R hearts in various models of obese-insulin resistance. However, the cardiac effects of diets in the I/R heart are still unsettled since several studies reported that high-caloric diet consumption might protect the heart from I/R injury. Although several therapeutic strategies such as anti-diabetic drugs, natural compounds as well as treadmill exercise have been proposed to exert cardioprotection in the I/R heart in obese-insulin resistant animals, some interventions including ischemic post-conditioning failed to protect the heart from I/R injury. In this comprehensive review, reports from both genetic deletion and dietary-induced obese-insulin resistant animal models regarding the effects of obese-insulin resistance on metabolic parameters, cardiac function, infarct size, and molecular mechanisms under I/R injury are summarized. Moreover, the effects of anti-diabetic drugs and other pharmacological interventions on these parameters in an obese-insulin resistant model under I/R injury are also comprehensively summarized and discussed.