Adenosine accumulation during ischemia and inflammation protects tissues from injury. In ischemic tissues adenosine accumulates due to inhibition of adenosine kinase, and in inflamed tissues adenosine is formed from adenine nucleotides that are released from many cells including platelets, mast cells, nerves, and endothelium. Nucleotides are rapidly converted to adenosine by a family of ecto-nucleotidases including CD39 and CD73. Activation of A₁ and possibly A₃ adenosine receptors (ARs) protects heart and other tissues by preconditioning through a pathway including protein kinase C and mitochondrial K_ATP channels. Activation of A_2A receptors limits reperfusion injury by inhibiting inflammatory processes in neutrophils, platelets, macrophages and T cells. Adenosine produces proinflammatory responses mediated by receptors that vary among species; A₃ and A_2B receptors mediate degranulation of rodent and human or canine mast cells, respectively. Novel adenosine receptor subtype–selective ligands have recently been developed. These include MRS1754 (A_2B blocker), MRS1220 (A₃ blocker), MRE 3008F20 (human A₃ blocker), MRS1523 (rat A₃ blocker), and ATL146e (A_2A agonist). These new pharmacologic tools will help investigators to sort out how adenosine protects tissues from injury and to identify new therapeutic agents that hold promise for the treatment of inflammatory and ischemic diseases.