Velocardiofacial syndrome (VCFS) is the most common known microdeletion in humans. It is also the most common known genetic risk factor for schizophrenia. The aim of this article is to describe the clinical characteristics of the syndrome, with emphasis on the myriad psychiatric disorders and abnormal behaviors from a developmental perspective. In addition, the possible pathways that lead to the psychotic symptoms and cognitive deficits are discussed. Guidelines are suggested to alert clinicians to the possibility of the presence of VCFS, and the cumulative clinical experience and limited research on psychiatric treatments for VCFS are presented. There is an urgent need to conduct treatment trials in this high-risk population.