Many obstructive airway disorders such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease (COPD) are characterized by mucous metaplasia of the airway epithelium and chronic mucus hypersecretion. Airway occlusion by mucus plugging has been reported in many cases of fatal asthma and conventional mucolytic therapies have been unable to significantly affect mucus-related airway obstruction. Recently, for the first time, direct evidence was presented for improvement of mucus related airway obstruction in a murine model of asthma, highlighting the potential usefulness of therapeutically targeting mucus hypersecretion. We review the emerging targets for inhibition of mucus hypersecretion and discuss some of the recent published scientific literature and patent applications in this field, to provide a framework for further drug discovery in mucus modulation.