Respiratory diseases such as asthma and COPD (chronic obstructive pulmonary disease) are characterized by increased numbers of goblet cells and excessive mucus production, which contribute to the underlying disease pathology. Mucins form a major component of the mucus contributing to its viscoelastic properties, and in the airways the mucins MUC5AC and MUC5B are found at increased levels in both asthmatic and COPD subjects. A diverse range of stimuli have been shown to regulate MUC5AC expression and cause increases in the number of mucus-producing goblet cells. Perhaps the best characterized of these mediators is the cytokine IL (interleukin)-13, which causes increases in MUC5AC-expressing goblet cells in the airways. Several transcription factors have been linked with goblet cell formation and mucus production and include STAT6 (signal transducer and activator of transcription 6), FOXA2 (forkhead box A2) and the SPDEF [SAM (sterile alpha motif) domain-containing prostate-derived Ets factor]. In mouse airways, goblet cells are normally rare or absent, but increase rapidly in number in response to certain stimuli. The origins of these goblet cells are not well understood, although Clara cells and ciliated cells have been implicated as goblet cell progenitors. An understanding of the origin and processes regulating goblet cell formation in human airway epithelial cells has important implications for the identification of therapeutic targets to treat respiratory diseases.