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: A(1) and A(3) 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 A(1) and to some extent A(3) 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 A(2) 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 A(1) 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.