The broad spectrum anti-inflammatory actions of adenosine A(2A) receptor agonists are well described. The wide distribution of this receptor, however, suggests that the therapeutic potential of these agents is likely to reside in topical treatments to avoid systemic side effects associated with oral administration. Adenosine A(2A) receptor agonists have been assessed as topical agents: GW328267X (GSK; allergic rhinitis and asthma), UK-432097 (Pfizer; chronic obstructive pulmonary disease [COPD]) and Sonedenoson (MRE0094, King Pharmaceuticals; wound healing). All trials failed to achieve effects against the desired clinical end points. This broad-based review will discuss general principles of chemical design of topically applied agents and potential therapeutic topical applications of current adenosine A(2A) receptor agonists. Potential factors contributing to the lack of efficacy in the above clinical trials will be discussed together with design principles, which may influence efficacy in disease states. Our analysis suggests that adenosine A(2A) receptor agonists have a wide therapeutic potential as topical agents in a wide variety of diseases, such as neutrophil-dependent lung diseases (acute lung injury, exacerbations in asthma and COPD), allergic rhinitis, glaucoma and wound repair. Factors that will influence topical activity include formulation, tissue retention, compound potency, receptor kinetics and pharmacokinetics.