Myocardial ischemia is associated with profound tissue hypoxia due to an imbalance in oxygen supply and demand, and studies of hypoxia-elicited adaptive responses during myocardial ischemia revealed a cardioprotective role for the signaling molecule adenosine. In ischemic human hearts, the A2B adenosine receptor (ADORA2B) is selectively induced. Functional studies in genetic models show that ADORA2B signaling attenuates myocardial infarction by adapting metabolism towards more oxygen efficient utilization of carbohydrates. This adenosine-mediated cardio-adaptive response involves the transcription factor hypoxia-inducible factor HIF1α and the circadian rhythm protein PER2. In this article, we discuss advances in the understanding of adenosine-elicited cardioprotection with particular emphasis on ADORA2B, its downstream targets, and the implications for novel strategies to prevent or treat myocardial ischemia.