The purpose of this study was to identify the brain regions invoked when subjects attempt to learn verbal materials for a subsequent memory test. Twelve healthy subjects undertook two different tasks: reading and encoding of word pairs, while they were being scanned using [15O]H2O positron emission tomography (PET). As expected, the encoding pairs were remembered much better (recall 39% vs. 8%; P < 0.001) than reading pairs in a subsequent memory test. The encoding scans, as compared to reading scans, showed activation of the left prefrontal cortex, the anterior cingulate cortex and the left medial temporal cortex. The left prefrontal activations were in two discrete regions: (i) a left anterior and inferior left prefrontal (Brodmann's areas 45, 46) which we attribute to semantic processing; and (ii) a left posterior mid-frontal region (BA 6, 44) which may reflect rote rehearsal. We interpret the data to suggest that when subjects use cognitive strategies of semantic processing and rote-rehearsal to learn words, they invoke discrete regions of the left prefrontal cortex. And this activation of the left prefrontal cortex along with the medial temporal region leads to a neurophysiological memory trace which can be used to guide subsequent memory retrieval.