Lesional and electrophysiological data implicate a role for the cerebral cortex in the initiation and modulation of human swallowing, and yet its functional neuroanatomy remains undefined. We therefore conducted a functional study of the cerebral loci processing human volitional swallowing with 15O-labeled water positron emission tomography (PET) activation imaging. Regional cerebral activation was investigated in 8 healthy right handed male volunteers with a randomized 12-scan paradigm of rest and water swallows (5 ml/bolus, continuous infusion) at increasing frequencies of 0.1, 0.2, and 0.3 Hz, which were visually cued and monitored with submental electromyogram (EMG). Group and individual linear covariate analyses were performed with SPM96. In five of eight subjects, the cortical motor representation of pharynx was subsequently mapped with transcranial magnetic stimulation (TMS) in a posthoc manner to substantiate findings of hemispheric differences in sensorimotor cortex activation seen with PET. During swallowing, group PET analysis identified increased regional cerebral blood flow (rCBF) (P < 0.001) within bilateral caudolateral sensorimotor cortex [Brodmann's area (BA) 3, 4, and 6], right anterior insula (BA 16), right orbitofrontal and temporopolar cortex (BA 11 and 38), left mesial premotor cortex (BA 6 and 24), left temporopolar cortex and amygdala (BA 38 and 34), left superiomedial cerebellum, and dorsal brain stem. Decreased rCBF (P < 0.001) was also observed within bilateral posterior parietal cortex (BA 7), right anterior occipital cortex (BA 19), left superior frontal cortex (BA 8), right prefrontal cortex (BA 9), and bilateral superiomedial temporal cortex (BA 41 and 42). Individual PET analysis revealed asymmetric representation within sensorimotor cortex in six of eight subjects, four lateralizing to right hemisphere and two to left hemisphere. TMS mapping in the five subjects identified condordant interhemisphere asymmetries in the motor representation for pharynx, consistent with the PET findings. We conclude that volitional swallowing recruits multiple cerebral regions, in particular sensorimotor cortex, insula, temporopolar cortex, cerebellum, and brain stem, the sensorimotor cortex displaying strong degrees of interhemispheric asymmetry, further substantiated with TMS. Such findings may help explain the variable nature of swallowing disorders after stroke and other focal lesions to the cerebral cortex.