Airway mucus has a key role in protective innate immune responses, but excessive mucus production and secretion in proximal and in distal airways are associated with disabling symptoms (cough and sputum), lung function decline, exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD). Cellular and molecular mechanisms leading to mucin production and secretion have largely been identified using cultured epithelial cells and animal models. Cigarette smoke and microbial products are potent triggers of mucin production, which involves recognition of specific molecular patterns by cognate receptors and activation of metalloproteases at the epithelial cell surface, leading to epidermal growth factor receptor activation and mucin mRNA and protein synthesis. After mucin synthesis has occurred, mucins are tightly packed into intracytoplasmic granules. Many stimuli induce secretion of mucin granules from epithelial cells, but neutrophil serine proteases are the most potent inducers of mucin secretion. Neutrophils recruited to the airway epithelium also promote mucin production via neutrophil proteases and oxidative stress. Several drugs currently available for the treatment of COPD patients reduced mucus hypersecretion in preclinical models relevant to COPD, but their effects on mucus hypersecretion in humans have not been assessed. Testing the effects of these drugs and of novel molecules designed for reducing mucus production and/or secretion will require performing specifically designed clinical trials. These trials will be necessary to explore the hypothesis that reducing mucus hypersecretion is beneficial in COPD patients.