Adenosine is a purine nucleoside that is expressed in all cells of the body and involved in a wide range of physiological processes. The effects of adenosine are mediated predominantly through specific cell surface receptors of which four subtypes (A₁, A_2A, A_2B and A₃) have been described. It is now well recognised that extracellular levels of adenosine markedly increase under metabolically stressful conditions, such as hypoxia and inflammation, and whilst an acutely elevated level of extracellular adenosine is considered to mediate anti-inflammatory and protective effects, chronic accumulation has been associated with pathological consequences. In asthmatic subjects, it has been demonstrated that adenosine levels in bronchoalveolar lavage fluid and exhaled breath condensate are significantly higher than those present in healthy subjects and current evidence strongly suggests that it may contribute to the pathogenesis of asthma. For example, it has been recognised for many years that inhalation of adenosine 5′-monophosphate (AMP) (5′-nucleotidase in the lung rapidly hydrolyses AMP to adenosine) in asthmatic but not healthy subjects results in dose-related bronchoconstriction and has also been shown to increase airway eosinophilia. The potent bronchoconstriction induced by AMP in asthmatic subjects has been suggested to be mediated predominantly by mast cell degranulation resulting from adenosine A_2B receptor activation, and in light of recent evidence, possibly also through a direct effect on airway smooth muscle via the A₁ receptor. Furthermore, plasma adenosine levels rapidly increase following allergen challenge in asthmatic subjects, raising the possibility that endogenous adenosine may even be directly involved in the early-phase bronchoconstrictor response to allergen, a suggestion supported in allergic rabbits by use of an anti-sense oligonucleotide directed against the adenosine A₁ receptor. Moreover, it has recently been reported that the concentrations of adenosine are increased in both plasma and exhaled breath condensate during exercise-induced bronchoconstriction in subjects with asthma, thus providing further evidence that endogenous adenosine may be involved in asthma. The accumulation of evidence implicating a role for adenosine in the pathogenesis of asthma has led to investigations into all adenosine receptor subtypes as potential therapeutic targets for the treatment of asthma. Selective A₁ receptor antagonists are currently in preclinical development since adenosine has been shown experimentally to mediate various features of asthma through this receptor such as bronchoconstriction and mucus secretion. An inhaled antisense oligonucleotide against the A₁ receptor reached Phase II of clinical development but failed to demonstrate sufficient efficacy. However, the xanthine derivative bamifylline is approved for the treatment of asthma in Europe and it has been demonstrated that it is a selective antagonist at the A₁ receptor, in contrast to theophylline, which is a non-selective adenosine receptor antagonist, suggesting that blockade of the A₁ receptor is of therapeutic benefit. The A_2A receptor is expressed on most inflammatory cells implicated in asthma, and as A_2A stimulation activates adenylate cyclase and consequently elevates cAMP, selective A_2A receptor agonists have now reached clinical development. However, initial reports concerning their efficacy are inconclusive. A_2B receptor antagonists are also under investigation based on the rationale that inhibiting the effects of adenosine on mast cells would be beneficial, in addition to other reported pro-inflammatory effects mediated by the A_2B receptor on cells such as airway smooth muscle and epithelial cells. Whilst the effects in pre-clinical models are promising, their efficacy in the clinical setting has also yet to be reported. Finally, adenosine A₃ receptor stimulation has been demonstrated to mediate inhibitory effects on eosinophils since it also elevates cAMP. However, some experimental reports suggest that A₃ antagonists mediate anti-inflammatory effects, thus the rationale for A₃ receptor ligands as therapeutic agents remains to be determined. In conclusion, establishing the precise role of adenosine in the pathogenesis of asthma and developing appropriate subtype selective agonists/antagonists represents an exciting opportunity for the development of novel therapeutics for the treatment of asthma.