This chapter discusses the chromosome 22q11.2 deletion syndrome, the most common microdeletion syndrome which affects nearly every organ system and requires multidisciplinary care. The most common clinical features associated with 22q11.2 deletion syndrome are immunodeficiency, congenital heart disease, palatal defects, low calcium levels, kidney anomalies, and feeding difficulties. Early recognition of the existence of this deletion is imperative so that treatment can be initiated, thus preventing or lessening complications. Most deletions (93%) occur as a de novo or random event resulting from structural features within the 22q11.2 region. Prenatal genetic counseling for the general population should be offered when anatomic abnormalities are identified on fetal ultrasonography or when significant findings are present in a parent after a careful family history.