Taken together, these data demonstrate that activation of basolateral Ca2+-activated KCNN4 K+ channels by 1-EBIO potentiates CFTR-mediated Cl− secretion induced by cAMP-mediated and cholinergic activation in native CF rectal tissues that express mutant CFTR proteins with residual Cl− channel function. Here, KCNN4 is linked to cystic fibrosis.