Researchers have long debated whether knowledge about the self is unique in terms of its functional anatomic representation within the human brain. In the context of memory function, knowledge about the self is typically remembered better than other types of semantic information. But why does this memorial effect emerge? Extending previous research on this topic (see Craik et al., 1999), the present study used event-related functional magnetic resonance imaging to investigate potential neural substrates of self-referential processing. Participants were imaged while making judgments about trait adjectives under three experimental conditions (self-relevance, other-relevance, or case judgment). Relevance judgments, when compared to case judgments, were accompanied by activation of the left inferior frontal cortex and the anterior cingulate. A separate region of the medial prefrontal cortex was selectively engaged during self-referential processing. Collectively, these findings suggest that self-referential processing is functionally dissociable from other forms of semantic processing within the human brain.