Adenosine, a purine nucleoside, is ubiquitous in the body, and is a critical component of ATP. Its concentration jumps 100-fold during periods of oxygen depletion and ischemia. There are four adenosine receptors: A₁ and A₃ coupled to G_i/o and the high-affinity A_2A and low-affinity A_2B coupled to G_s. Adenosine is one of three autacoids released by ischemic tissue which are important triggers of ischemic preconditioning (IPC). It is the A₁ and to some extent A₃ receptors which participate in the intracellular signaling that triggers cardioprotection. Unlike bradykinin and opioids, the other two autacoids, adenosine is not dependent on opening of mitochondrial K_ATP channels or release of reactive oxygen species (ROS), but rather activates phospholipase C and/or protein kinase C (PKC) directly. Another signaling cascade at reperfusion involves activated PKC which initiates binding to and activation of an A₂ adenosine receptor that we believe is the A_2B. Although the latter is the low-affinity receptor, its interaction with PKC increases its affinity and makes it responsive to the accumulated tissue adenosine. A_2B agonists, but not adenosine or A₁ agonists, infused at reperfusion can initiate this second signaling cascade and mimic preconditioning’s protection. The same A_2B receptors are critical for postconditioning’s protection. Thus adenosine is both an important trigger and a mediator of cardioprotection.