Unilateral spatial neglect involves a failure to report or orient to stimuli in the contralesional (left) space due to right brain damage, with severe handicap in everyday activities and poor rehabilitation outcome. Because behavioral studies suggest that prism adaptation may reduce spatial neglect, we investigated the neural mechanisms underlying prism effects on visuo-spatial processing in neglect patients. We used functional magnetic resonance imaging (fMRI) to examine the effect of (right-deviating) prisms on seven patients with left neglect, by comparing brain activity while they performed three different spatial tasks on the same visual stimuli (bisection, search, and memory), before and after a single prism-adaptation session. Following prism adaptation, fMRI data showed increased activation in bilateral parietal, frontal, and occipital cortex during bisection and visual search, but not during the memory task. These increases were associated with significant behavioral improvement in the same two tasks. Changes in neural activity and behavior were seen only after prism adaptation, but not attributable to mere task repetition. These results show for the first time the neural substrates underlying the therapeutic benefits of prism adaptation, and demonstrate that visuo-motor adaptation induced by prism exposure can restore activation in bilateral brain networks controlling spatial attention and awareness. This bilateral recruitment of fronto-parietal networks may counteract the pathological biases produced by unilateral right hemisphere damage, consistent with recent proposals that neglect may reflect lateralized deficits induced by bilateral hemispheric dysfunction.