This study used positron emission tomography (PET) to identify the brain substrate of self-referential reflective activity and to investigate its relationship with brain areas that are active during the resting state. Thirteen healthy volunteers performed reflective tasks pertaining to three different matters (the self, another person, and social issues) while they were scanned. Rest scans were also acquired, in which subjects were asked to simply relax and not think in a systematic way. The mental activity experienced during each scan was assessed with rating scales. The results showed that, although self-referential thoughts were most frequent during the self-referential task, some self-referential reflective activity also occurred during rest. Compared to rest, performing the reflective tasks was associated with increased blood flow in the dorsomedial prefrontal cortex, the left anterior middle temporal gyrus, the temporal pole bilaterally, and the right cerebellum; there was a decrease of blood flow in right prefrontal regions and in medial and right lateral parietal regions. In addition, the ventromedial prefrontal cortex (VMPFC) (1) was more active during the self-referential reflective task than during the other two reflective tasks, (2) showed common activation during rest and the self-referential task, and (3) showed a correlation between cerebral metabolism and the amount of self-referential processing. It is suggested that the VMPFC is crucial for representing knowledge pertaining to the self and that this is an important function of the resting state.