Comportment can be understood through analysis of its individual components: insight, judgment, self-awareness, social adaptation, and empathy. The case of Phineas Gage has served as the guiding compass towards our understanding of the prefrontal cortex as a region critical for comportment. Modern neuroimaging using the skull of Gage has shown bihemispheric prefrontal lesions involving the orbitofrontal cortex, the medial frontal cortex, and the anterior cingulate gyrus. A variety of diseases that preferentially affect the prefrontal cortex and that result in increased aggression, loss of empathy, and disinhibition have provided neurologists with insight into the brain structures responsible for comportment. This chapter discusses the pathogenesis of developmental disorders such as autism and Asperger's Syndrome (AS), degenerative processes such as frontotemporal dementia (FTD), physical injury to the prefrontal cortex, and schizophrenia as well as relevant functional neuroimaging studies.