Objectives: To identify potential molecular genetic determinants of cardiovascular ischemic tolerance in wild-type and transgenic hearts overexpressing A1 adenosine receptors (A1ARs). Methods: cDNA microarrays were used to explore expression of 1824 genes in wild-type hearts and ischemia-tolerant mouse hearts overexpressing A1ARs. Results: Overexpression of A1ARs reduced post-ischemic contractile dysfunction, limited arrhythmogenesis, and reduced necrosis by ∼80% in hearts subjected to 30 min global ischemia 60 min reperfusion. Cardioprotection was abrogated by acute A1AR antagonism, and only a small number (19) of genes were modified by A1AR overexpression in normoxic hearts. Ischemia-reperfusion significantly altered expression of 75 genes in wild-type hearts (14 induced, 61 down-regulated), including genes for metabolic enzymes, structural/motility proteins, cell signaling proteins, defense/growth proteins, and regulators of transcription and translation. A1AR overexpression reversed the majority of gene down-regulation whereas gene induction was generally unaltered. Additionally, genes involved in cell defence, signaling and gene expression were selectively modified by ischemia in transgenic hearts (33 induced, 10 down-regulated), possibly contributing to the protected phenotype. Real-time PCR verified changes in nine selected genes, revealing concordance with array data. Transcription of the A1AR gene was also modestly reduced post-ischemia, consistent with impaired functional sensitivity to A1AR stimulation Conclusions: Data are presented regarding the early post-ischemic gene profile of intact heart. Reduced A1AR transcription is observed which may contribute to poor outcome from ischemia. A1AR overexpression selectively modifies post-ischemic gene expression, potentially contributing to ischemic-tolerance.