Airway secretions are produced by glandular and epithelial exocytosis and vascular permeability. Each process plays a unique role in different disease states, and so treatment must be tailored to the pathophysiological mechanism(s). In acute allergic rhinitis, the watery rhinorrhea is predominantly plasma with only about one-third derived from histamine-induced nociceptive afferent nerve and parasympathetic reflexes. The acetylcholine acts on muscarinic M3 receptors on glands to stimulate exocytosis from both mucous and serous cells. Parasympathetic, cholinergic reflex-mediated glandular secretion responds very well to anticholinergic drugs. More chronic inflammation as seen in chronic rhinosinusitis and bronchitis leads to goblet cell hyperplasia and increased secretion of mucin 5AC (MUC5AC), a secreted, gel-forming mucin that contains many serine–threonine repeats that are studded with large O-linked carbohydrate groups. Progressively worsening inflammation leads to the addition of sialic acid and sulphate to generate acidic mucins. The protein chains are cross-linked by disulphide bonds to form large, buoyant islands that float on the epithelial lining fluid. These sticky macromolecules form complexes with albumin and neutrophil-derived DNA, F-actin, and proteolytic enzymes, creating mucoclots. These tenacious, viscous, mucoclots can adhere to epithelial linings, which may lead to occlusion of small airways that causes reduced airflow in chronic obstructive pulmonary disease and asthma. Mucous plugging is a problem leading to the overwhelming mucous hypersecretion and solidification of ‘end-stage’ acute asthma attacks. Mucous hypersecretion of this severity has been correlated with increased morbidity and mortality in lung disease. Anticholinergic drugs are essential therapies in these conditions. Other medications for mucous hypersecretion include expectorants, anti-inflammatory agents, macrolides, inhaled DNase, and a host of unproven products. Information about signal transduction, transcriptional regulation, and mucin synthesis has provided a framework for understanding the excess production of goblet cell MUC5AC in disease, and has identified potential targets for future drug therapy.