Recent studies demonstrated that resveratrol, a grape-derived polyphenolic phytoalexin, could pharmacologically precondition (PC) the heart through a nitric oxide (NO)-dependent mechanism. Since, adenosine receptors have been found to play a role in PC, this study examined if adenosine receptors could play any role in resveratrol PC. The rats were randomly assigned to one of the following groups: perfused for 15 min with i) Krebs Ringer bicarbonate (KHB) only ii) KHB containing 10 µM resveratrol; iii) 10 µM resveratrol + 1 µM 8-cyclopentyl-1,3-dimethylxanthine (CPT), adenosine A₁ receptor blocker; iv) 10 µM resveratrol + 1 µM 8-(3-chlorostysyl) caffeine (CSC), adenosine A_2a receptor blocker; v) 10 µM resveratrol + 1 µM 3-Ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicar-boxylate (MRS 1191), adenosine A₃ receptor blocker; and vi) 10 µM resveratrol+3 µM 2-(4-Morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY 294002), a phospho inositol (PI)-3-kinase inhibitor. All hearts were then subjected to 30 min ischemia followed by 2 h reperfusion. The results demonstrated significant cardioprotection with resveratrol as evidenced by improved ventricular recovery, and reduced infarct size and cardiomyocyte apoptosis. CPT and MRS 1191, but not CSC, abrogated the cardioprotective abilities of resveratrol suggesting a role of adenosine A₁ and A₃ receptors in resveratrol PC. Resveratrol induced the expression of Bcl₂, and caused its phosphorylation along with phosphorylation of CREB, Akt and Bad. CPT blocked the phosphorylation of Akt and Bad without affecting CREB, while MRS 1191 blocked phosphorylation of all the compounds including CREB. LY 294002 partially blocked the cardioprotective abilities of resveratrol. The results indicate that resveratrol preconditions the heart through the activation of adenosine A₁ and A₃ receptors, the former transmitting a survival signal through PI-3-kinase-Akt-Bcl₂ signaling pathway, while the latter protects the heart through a CREB-dependent Bcl₂ pathway in addition to Akt-Bcl₂ pathway. Key Words: Resveratrol, Adenosine A₁ and A₃ Receptors. Akt, CREB, BAD, BCL₂, Apoptosis