CFTR is an apically resident ion channel whose activity is regulated by the activation of the cAMP mediated second messenger cascade. As depicted in textbooks, the cAMP mediated signaling cascade appears deceptively simple, yet, our growing understanding of this pathway shows it to be much more complicated and finely tuned than originally thought. The intent of this review is to evaluate our current understanding of the cAMP mediated signaling as it relates to the secretion of mucin and chloride, two compounds whose regulated secretion is altered in cystic fibrosis.