The exocrine salivary glands of mammals secrete K⁺ by an unknown pathway that has been associated with HCO₃^- efflux. However, the present studies found that K⁺ secretion in the mouse submandibular gland did not require HCO₃^-, demonstrating that neither K⁺/HCO₃- cotransport nor K⁺/H⁺ exchange mechanisms were involved. Because HCO₃^- did not appear to participate in this process we tested whether a K channel is required. Indeed, K⁺ secretion was inhibited more than 75% in mice with a null mutation in the maxi-K, Ca²⁺-activated K channel (KCa1.1) but was unchanged in mice lacking the intermediate conductance IK_Ca1 channel (K_Ca3.1). Moreover, paxilline, a specific maxi-K channel blocker, dramatically reduced the K⁺ concentration in submandibular saliva. The K⁺ concentration of saliva is well-known to be flow-rate dependent, the K⁺ concentration increasing as the flow decreases. The flow-rate dependence of K⁺ secretion was nearly eliminated in K_Ca1.1 null mice, suggesting an important role for K_Ca1.1 channels in this process as well. Importantly, a maxi-K-like current had not been previously detected in duct cells, the theoretical site of K⁺ secretion, but we found that K_Ca1.1 channels localized to the apical membranes of both striated and excretory duct cells, but not granular duct cells, using immunohistochemistry. Consistent with this latter observation, maxi-K currents were not detected in granular duct cells. Taken together, these results demonstrate that the secretion of K⁺ requires and is likely mediated by K_Ca1.1 potassium channels localized to the apical membranes of striated and excretory duct cells in the mouse submandibular exocrine gland.