Adenosine is an endogenous purine metabolite whose concentration in human blood plasma rises from nanomolar to micromolar concentrations during the inflammatory process. Leukocytes express seven-transmembrane adenosine receptors whose engagement modulates Toll-like receptor-mediated cytokine responses, in part via modulation of intracellular cyclic adenosine monophosphate. Adenosine analogs are used clinically to treat arrhythmias and apnea of prematurity. Herein, we consider the potential of adenosine analogs as innate immune response modifiers to prevent and/or treat infection.