Methods and compositions for modulating mucin secretion by respiratory system cells are provided. In the subject methods, an effective amount of an hCLCA2 (or homolog thereof) modulatory agent is contacted with the cell to modulate mucin secretion, e.g., decrease or increase mucin secretion, by the cell. The subject methods find use in a variety of different applications, including the treatment of disease conditions associated with respiratory system mucin secretion, e.g., mucin hyper- or hyposecretion. Also provided are methods of screening for respiratory system mucin secretion modulatory agents. Finally, mCLCA4 and non-human homologs thereof, as well as nucleic acid compositions encoding the same, are provided.