Functional imaging data suggest that the core network engaged in verbal semantic memory (SM) processing encompasses frontal and temporal lobe structures, with a strong left lateralization in normal right handers. The impact of long term temporal lobe epilepsy (TLE) on this network has only partly been elucidated. We studied verbal SM in 50 patients with chronic, intractable TLE (left TLE=26, right TLE=24) and 35 right handed normal controls using a verbal fMRI semantic decision paradigm. All patients had language lateralized to the left hemisphere, as verified by the intracarotid amobarbital procedure. Within and between group analyses showed remarkable, group-specific activation profiles. The control group activated frontal and temporal areas bilaterally, with a strong left predominance. Left TLE patients showed a shift of activations of left frontal and medial temporal areas to homologous regions in the right hemisphere. Furthermore, left TLE subjects utilized subcortical structures such as the thalamus and putamen to accomplish the verbal SM task. Contrastively, the activation pattern of right TLE patients resembled that of normal controls, but exhibited "hypofrontality" with a shift from frontal to posterior regions in the temporal, parietal and occipital lobe. Our results show that chronic epileptic activity originating from temporal seizure foci is associated with an alteration of neural circuits which support semantic language processing and that side of seizure focus has a specific impact on the resulting activation network. These findings presumably result from morphological changes and from functional reorganization which are both inherent to chronic TLE.