Mucus hypersecretion is a prominent feature of chronic inflammatory diseases of the airways, including asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis, but little is known about the effects of current therapies for airway disease because of the difficulties in quantifying mucus hypersecretion in clinical studies. Anticholinergics may reduce mucus hypersecretion, whereas beta2 agonists and mucolytics have little obvious effect. Corticosteroids are highly effective in inhibiting mucus hypersecretion in asthma by suppressing the underlying inflammatory process, but are ineffective in COPD and cystic fibrosis. Novel approaches in the future may include inhibition of sensory neuropeptides by tachykinin antagonists, modulators of sensory nerves or K+ channel openers. Inhibition of Th2 cytokines (interleukin [IL]4, IL9, IL13) may also be effective in asthma. In COPD inhibition of neutrophil-derived proteases by small molecule inhibitors or inhibiting neutrophilic inflammation in the airways by reducing neutrophil chemotaxis may also be effective strategies. Several novel targets involved in mucus hypersecretion have recently been identified, including epidermal growth factor receptors, MARCKs, Ca2+-activated Cl- channels and mitogen-activated protein kinases. However, the clinical benefits from inhibiting mucus hypersecretion are still not certain, casting some doubts on this therapeutic approach.