Recent studies have used spatial reorientation task paradigms to identify underlying cognitive mechanisms of navigation in children, adults, and a range of animal species. Despite broad interest in this task across disciplines, little is known about the brain bases of reorientation. We used functional magnetic resonance imaging to examine neural activity in adults during a virtual reality version of the reorientation task. Three environments that varied in the cues provided were studied: a rectangular room with 4 identical gray walls (Geometry), a square room with 3 gray walls and 1 red wall (Feature), and a rectangular room with 3 gray walls and 1 red wall (Feature + Geometry). Multiple areas within the medial temporal lobe (MTL) showed increased activation when a feature was present compared with when reorientation was based only on geometric cues. In contrast, reliance on geometric cues significantly activated a number of non-MTL structures, including the prefrontal cortex and inferior temporal gyrus. These results provide neural evidence for processing differences between the 2 types of cue as well as insight into developmental and comparative aspects of reorientation. (Contains 2 tables and 4 figures.)