Abstract: Epidemiological studies suggest that regular moderate consumption of red wine confers cardioprotection but the mechanisms involved in this effect remain unclear. Recent studies demonstrate the presence of melatonin in wine. We propose that melatonin, at a concentration found in red wine, confers cardioprotection against ischemia–reperfusion injury. Furthermore, we investigated whether both melatonin and resveratrol protect via the activation of the newly discovered survivor activating factor enhancement (SAFE) prosurvival signaling pathway that involves the activation of tumor necrosis factor alpha (TNFα) and the signal transducer and activator of transcription 3 (STAT3). […] Both resveratrol and melatonin, at concentrations found in red wine, significantly reduced infarct size compared with control hearts in wild-type mouse hearts (25 ± 3% and 25 ± 3% respectively versus control 69 ± 3%, P < 0.001) but failed to protect in TNF receptor 2 knockout or STAT3-deficient mice. Furthermore, perfusion with either melatonin or resveratrol increased STAT3 phosphorylation prior to ischemia by 79% and 50%, respectively (P < 0.001 versus control). Our data demonstrate that both melatonin and resveratrol, as found in red wine, protect the heart in an experimental model of myocardial infarction via the SAFE pathway. [...] Conclusion In conclusion, our data strongly support the fact that the presence of melatonin in red wine, together with resveratrol, may contribute to the red wine hypothesis it also suggests that melatonin is a superior antioxidant present in red wine and contributes to the red wine hypothesis. Furthermore, we have delineated a novel mechanism by which low amounts of melatonin and resveratrol protect the heart via the activation of the powerful prosurvival SAFE pathway, which involves the activation of both TNFα and STAT3. Our data provide exciting novel insight into the use of natural compounds in the treatment of cardiac disease.