Several recent studies have investigated whether knowledge representation turns possible within virtual reality simulated environments. According to these affirmative results different clinical applications were developed in psychology. Among these applications virtual reality seems to have a specific role in assessment and treatment of neuropsychological diseases. This chapter will firstly investigate possibilities and challenges carried from virtual-reality-based neuropsychological application focusing both on patient's and therapist's point of view. Afterward it will provide a survey of research and intervention application examples. More in detail a clear explanation of contribution goals will be discussed, in order to place research and applied works within a cognitive neuroscience frame of reference, according with their usefulness and effectiveness in clinical treatment. Fulfilling these objectives neuropsychological virtual reality approaches in memory, motor abilities, executive functions and spatial representation will be shown.