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Accumulation of thick, sticky mucus is a hallmark of the genetic disease cystic fibrosis (CF) and has a central role in CF pathophysiology. Mutations in the CF transmembrane regulator (CFTR) ion channel are known to result in abnormally thick and sticky mucus; however, why mucus accumulates in CF is still not completely understood. In this issue of the JCI, Garcia and colleagues show that mucin — the heavily glycosylated protein contained within mucus — requires CFTR and bicarbonate in order to be released from mouse intestine (see the related article beginning on page 2613). The authors propose a model whereby CFTR-mediated bicarbonate secretion must be concurrent with mucin exocytosis for proper mucin release.