Activation of Cl− channels in salivary acinar and duct cells is essential for saliva production. Anion efflux through an apical Ca2+-dependent Cl− channel (CaCC) is the rate limiting step for fluid secretion by acinar cells. The ionic composition of the primary saliva is then modified by salivary ducts. CaCC may support electrolyte reabsorption by duct cells of several types that constitute the duct system. The molecular identity of salivary CaCC is currently under vigorous examination. Here we explored the function of Best2, a member of the Bestrophin family of CaCCs, in the mouse submandibular salivary gland. Heterologous expression of the Best2 transcript in HEK293 cells produced Ca2+-activated Cl− current with the biophysical and pharmacologic properties that closely resembled the current found in native salivary cells. A recently developed Best2−/− mouse where the gene was disrupted by insertion of Lac Z was used to further characterize the role of this channel in the exocrine salivary gland. Even though Best2 expression was abolished, the amplitude and properties of the Ca2+-activated Cl− current in the acinar cells obtained from Best2-deficient mice were the same as the Ca2+-activated Cl− current in wildtype cells. Consistent with the observation the fluid secretion rate was not significantly different in Best2 null mice. Best2 gene was highly expressed in the duct cells of submandibular glands as revealed by X-gal staining. While, the ionic composition and osmolality of the saliva was not significantly altered in mice lacking Best2, the possibility of the functional compensation has been investigated in duct cells. Granular duct cells failed to present Ca2+-sensitive component of anion conductance. The properties of Cl− channels in intercalated, striated and excretory duct cells are currently under investigation.