The cystic fibrosis transmembrane conductance regulator (CFTR) produces a cAMP-dependent Cl^- conductance of distinct properties that is essential for electrolyte secretion in human epithelial tissues. However, the functional consequences of CFTR-expression are multifaceted, encompassing much more than simply supplying a cellular cAMP-regulated Cl^- conductance. When we expressed CFTR in Xenopus oocytes, we found that extracellular acidic pH activates a Cl^- conductance that is, however, not due to CFTR Cl^- currents. The proton activated Cl^- conductance showed biophysical and pharmacological features of a Ca²⁺ dependent Cl^- conductance (CaCC) and was clearly Ca²⁺ dependent. In contrast to extracellular acidification, intracellular acid pH did not activate CaCC. Surprisingly, apart from fully functional wtCFTR, also the trafficking mutant F508del-CFTR was able to confer proton sensitivity, while the gating mutant G551D-CFTR did not generate a proton activated Ca²⁺ dependent Cl^- conductance. CFTR may induce or augment extracellular proton sensing by translocating proton receptors to the plasma membrane and by facilitating Ca²⁺ release from the endoplasmic reticulum. The data suggest the role of CFTR for pH sensing in bone cells and may provide a link to abnormal bone formation in cystic fibrosis.