Human lung cells exposed to pathogenic bacteria upregulate the production of mucin, the major macromolecular component of mucus. Generally this upregulation is beneficial for the host, however, in the lungs of cystic fibrosis patients, overproduction of mucin can lead to the plugging of pulmonary airways. Mucus plugging impedes airflow and creates an environment that is highly compartmentalized: those bacteria within the mucus layer are shielded from high doses of antibiotics whereas those outside the mucus are exposed. These conditions augment mutation rate and the development of drug resistance in bacteria that colonize the lungs of cystic fibrosis patients. While therapeutic inhibition of mucin induction would improve airflow and reduce antibiotic resistance in these patients, the challenge is to develop drugs that block excessive mucin production while leaving beneficial aspects of the response intact. To do this, we must understand the molecular mechanisms underlying mucin production. Here we review the signal transduction pathways that control mucin production in response to Gram-positive and Gram-negative bacteria.