Mucin, the major macromolecular component of mucus, is generally considered to be a protective substance. When overproduced in a variety of lung diseases, however, mucin gives rise to clinical problems such as airway obstruction and recurrent infection. Our approach to identifying drug targets for the control of mucin overproduction is the analysis of cellular signalling pathways linking stimuli in the diseased lung to mucin transcription. Here we show that mucin transcription in response to both gram-positive bacteria and tobacco smoke is mediated through activation of the epidermal growth factor receptor (EGFR). The mode of activation of EGFR in response to bacterial lipoteichoic acid involves cleavage of the transmembrane ligand HBEGF by ADAM 10, whereas the activation of EGFR in response to smoke involves cleavage of amphiregulin by ADAM 17.