While the ecological validity of virtual reality (VR) applications is usually assessed by behavioral data or interrogation, an alternative approach on a neuronal level is offered by brain imaging methods. Because it is yet unclear if 3D space in virtual environments is processed analogically to the real world, we conducted a study investigating virtual spatial processing in the brain using functional magnetic resonance imaging (fMRI). Results show differences in VR spatial brain processing as compared to known brain activations in reality. Identifying differences and commonalities of brain processing in VR reveals limitations and holds important implications for VR therapy and training tools. When VR therapy aims at the rehabilitation of brain function and activity, differences in brain processing have to be taken into account for designing effective VR training tools. Furthermore, for an evaluation of possible restoration effects caused by VR training, it is necessary to integrate information about the brain activation networks elicited by the training. The present study provides an example for demonstrating the benefit of fMRI as an evaluation tool for the mental processes involved in virtual environments.