Velo-cardio-facial syndrome (VCFS) is caused by an interstitial deletion from chromosome 22 at the 22q11 band. It is the most common microdeletion syndrome yet identified in humans, with a population prevalence of approximately 1 in 2,000 (Robin & Shprintzen, 2005). Velo-cardio-facial syndrome is known by a number of other names based on other reports in the literature that described individual components of the syndrome from a number of different perspectives. These include: DiGeorge syndrome, 22q11.2 deletion syndrome, Sedlačková syndrome, conotruncal anomalies face syndrome, and Cayler syndrome (Robin & Shprintzen, 2005). Structural anomalies affect nearly every part and system of the body and may include congenital heart disease, palatal defects, thymic hypoplasia, and endocrine disorders (Robin & Shprintzen, 2005). Velo-cardio-facial syndrome is the most common genetic cause of conotruncal heart anomalies and the most common genetic cause of cleft palate (Shprintzen et al., 2005) in addition to being the most significant genetic cause of mental illness yet identified. The earliest cases of VCFS to appear in the medical literature were probably those reported by Sedlačková in 1955 (E. Sedlačková, 1955). Sedlačková proposed a mechanism of neurologic and developmental anomalies that caused abnormalities of the palate leading to hypernasal speech and lack of facial animation caused by abnormal neurologic innervation (E. Sedlačková, 1967). The same disorder was described in 1968 by DiGeorge (DiGeorge, 1968) and by Kretschmer (Kretschmer, Say, Brown, & Rosen, 1968) who described endocrine and immunologic disorders associated with congenital heart disease. The 1st person, however, to delineate this disorder as a genetic syndrome was Strong (Strong, 1968), with his description of a single family with an affected mother and 3 affected children. Larger numbers of cases with broader phenotypic descriptions and multiple familial cases with a clear autosomal dominant pattern of inheritance followed (Shprintzen et al., 1978; Shprintzen, Goldberg, Young, & Wolford, 1981; Williams, Shprintzen, & Goldberg, 1985) thereby confirming that VCFS was a genetic syndrome. In the years that followed, the phenotypic spectrum of VCFS was expanded in a small series of papers.