The 22q11.2 Deletion Syndrome (22q11DS), previously referred to as velocardiofacial syndrome or DiGeorge syndrome, is complex and under-recognized. It is important that psychiatrists be familiar with it as it is characterized by an increased lifetime risk for psychiatric illnesses including schizophrenia, mood disorders, anxiety disorders, and disruptive behavioral disorders. Features in a child’s history, which may be suggestive of 22q11DS, including developmental features and common medical comorbidities are identified. A wide variety of cases highlight how this diagnosis is often missed, what the consequences of missed diagnosis are, and why there is the need for an interdisciplinary approach to diagnosis and treatment.