A mucus hypersecretory phenotype is a dominant characteristic of chronic airways diseases such as chronic bronchitis and asthma. This phenotype develops following chronic exposure of the respiratory tract to particulate matter, allergens, irritants and/or pathogens. The associated increase in the mucus-producing potential of the respiratory epithelium represents an innate host response that can be modulated by elements of the adaptive host response. Although elevation of mucus production is designed to protect the airways, increasing evidence suggests that in excess it can be detrimental to health. Considerable progress has been made over the past five years in understanding the mechanisms involved in the development and regulation of the hypersecretory phenotype. This progress has set the stage for the development of successful dedicated mucomodulatory strategies to counter the negative impact of excess mucus production in respiratory disease.