Life for most species is best in a very narrow range of pH. Departures of tissue pH from this narrow range are guarded against by various neural and physiological defense mechanisms. In the past few years, we have gained a much better understanding of what the sensory bases of the defenses against acid insults are. Specifically, several ion channels (TRPV1, Caterina et al., 1997; ASIC3, Waldmann et al., 1997; Ugawa, this issue) have been identified and cloned that respond to even moderately acidic pH. Less is known about the mechanisms monitoring tissue alkalinity. Although tissue acidity is the more common condition that is encountered in pathological situations, there are several conditions that give rise to alkaline tissue. Respiratory alkalosis due to hyperventilation, for instance gives rise to tingling in the extremities and lowered peripheral nerve thresholds (Tenny and Lamb, 1965; Mogyoros et al., 1997). Moreover, alkaline environmental insults to unprotected epithelium such as cornea and nasal mucosa give rise to behavioral defenses such as pain (Acosta et al., 2001) or apnea (Lindberg et al., 1987a) and the physiological defenses of vasodilatation (Izumi and Karita, 1993), tearing and increased mucociliary activity (Lindberg et al., 1987b). In the cranial region these defenses are mediated by the branches of the trigeminal nerve. Ammonia, for instance, activates fibers in the ethmoid branch of the trigeminal nerve (Sekizawa and Tsubone, 1994). To elucidate the mechanisms underlying trigeminal sensitivity to alkaline pH, responses of cultured rat trigeminal neurons to alkaline stimulation were measured using fluorescence imaging of intracellular calcium,[Ca2+] i (Kirifides et al., 2004) and intracellular pH (James-Kraacke, 1992). Using this approach, the influence of epithelial permeability barriers and potential stimulatory contributions of the epithelium were eliminated.