Background: In asthma and chronic obstructive pulmonary disease (COPD), airway mucus hypersecretion contributes to impaired mucociliary clearance, mucostasis and, potentially, the development of mucus plugging of the airways. Summary: Excess mucus production can be targeted via therapies that focus on inhibition mucin synthesis, via reducing expression of mucin (MUC) genes, and/or inhibition of mucin secretion into the airways. Key Messages: This review discusses a number of therapeutic approaches to reduce airway mucus in asthma and COPD, including the use of synthetic and natural products. In particular, it highlights areas where clinical trials of inhibitors of particular target molecules are lacking. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are an example of a targeted therapy that has been researched to reduce mucus synthesis, as have inhibitors of EGFR's downstream signalling pathways, for example, mitogen-activated protein kinase-13 and hypoxia inducible factor-1. However, their efficacy and safety profiles are currently not up to the mark. There is clinical potential in Bio-11006, which reduces mucus secretion via the inhibition of myristoylated alanine-rich C-kinase substrate and is currently in Phase IIb trial.