The human genome project, as well as advances in our understanding of asthma susceptibility, are yielding novel candidate targets for disease intervention. The normalization of up-regulated gene expression may treat or improve the disease outcome. However, only some of these gene product targets may be ‘tractable’, i.e. amenable to blockade by small, orally active, organic molecules. The remainder have been termed ‘non-tractable’.For over a decade, antisense oligonucleotides (ASONs) have been used as tools to evaluate the importance of specific gene productsin vitro. In recent years evidence has accumulated indicating their potential as a viable new therapeutic approach in their own right, being able to block ‘non-tractable’ targets as well as ‘tractable’ targets.Distribution, cell-specific uptake, and effectiveness of aerosolized phosphorothioate ASONs are currently being evaluated in animal models. The results demonstrate broad distribution throughout the lung, and uptake by all of the cell types examined to date. Functionality has been demonstrated against diverse targets, including nuclear transcription factors, tyrosine kinases, G-protein coupled receptors, cytokine receptors, growth factors, and chemokines.EPI-2010, a respirable ASON (RASON) against the adenosine A1receptor, is the first test case for this new class of respiratory therapeutics. The rationale for EPI-2010 is that overactivity of the adenosine-signaling pathway in asthmatic lungs contributes to airway inflammation and hyperresponsiveness. EPI-2010 binds to the initiation codon of the adenosine A1receptor mRNA, and thereby blocks translation and targets the message for degradation by RNase. EPI-2010 is apparently metabolized locally by endogenous nucleases confining its activity to the airways. Phase I clinical trials have shown EPI-2010 to be well-tolerated, with indications of efficacy.In conclusion, one important application of RASONs is in addressing up-regulated disease targets, only some of which are ‘tractable’ by small molecules. It is hoped that this will yield new therapeutic options to the benefit of patients with asthma and allergic disorders.