The 22q11.2 deletion syndrome represents a contiguous gene syndrome with a highly variable phenotype. To date, over 180 clinical features have been described. Studies have been done in order to identify the responsible genes. Several candidate genes such as TBX1 and COMT seem to be important in the development of the phenotype. One of the prevalent and serious problems encountered by patients with the 22q11.2 deletion is difficulty with speech. This may be due to a number of factors such as adenoid hypoplasia, muscle hypotonia, platybasia, upper airway asymmetry, and neuroanatomical abnormalities. The complex interaction of these factors leads to less favourable results after surgery to correct velopharyngeal insufficiency. This article offers a theoretical overview and proposes future research to investigate which factors are indeed responsible for the speech problems encountered by patients with the 22q11.2 deletion and identify responsible genes.