Given the strong association between obesity and cardiovascular diseases, and the fact that obese individuals are hyperleptinemic, in this mini review we summarize some of the conflicting studies related to leptin's impact on cardiac function and recent studies that have discovered novel cardioprotective effects of activating the brain leptin-melanocortin pathway following ischemic injury. This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.