Introduction: Evidence accumulated in the last decade has started to reveal the enormous complexity in the expression, interactions and functions of the large number of different mucins present in the different compartments of the human lower airways. This occurs both in normal subjects and in COPD patients in different clinical phases and stages of severity. Areas covered: We review the known physiological mechanisms that regulate mucin production in human lower airways of normal subjects, the changes in mucin synthesis/secretion in COPD patients and the clinical efficacy of drugs that modulate mucin synthesis/secretion. Expert opinion: It is evident that the old simplistic concept that mucus hypersecretion in COPD patients is associated with negative clinical outcomes is not valid and that the therapeutic potential of ‘mucolytic drugs’ is under-appreciated due to the complexity of the associated molecular network(s). Likewise, our current knowledge of the effects of the drugs already available on the market that target mucin synthesis/secretion/structure in the lower airways is extremely limited and often indirect and more well-controlled clinical trials are needed in this area.