Adenosine is a purine nucleoside, which is produced inside the body under metabolic stress like hypoxic conditions, acute or chronic inflammatory tissue insults. The synthesis of adenosine involves the catabolism of adenine nucleotides (ATP, ADP and AMP) by the action of extracellular ectonucleotidases i.e. CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5'-ectonucleotidase. Once adenosine is released in the extracellular environment, it binds to different types of adenosine (i.e. adenosine A(1), A(2A), A(2B) and A(3) receptors) receptors expressed on various innate immune cells [Neutrophils, macrophages, mast cells, dendritic cells and natural killer cells]. Thus, depending on the type of adenosine receptor to which it binds, adenosine modulates innate immune response during various inflammatory conditions [i.e. chronic (cancer, asthma) as well as acute (sepsis, acute lung injury) inflammatory diseases]. This review summarizes the effect of adenosine on innate immunity and the use of adenosine receptor specific agonists or antagonists in various immunologic disorders (asthma, cancer, HIV-1 infection) as future immunomodulatory therapeutics.