Structural and functional palatal anomalies are among the most common manifestations in velo-cardio-facial syndrome (VCFS), with cleft lip, cleft palate, and velopharyngeal dysfunction reported as features of affected patients. This chapter describes the spectrum of palatal phenotypes associated with VCFS and presents guidelines for their diagnosis and surgical management. The prevalence of 22q11 deletions among patients referred for evaluation of clefts of the secondary palate has been reported to be approximately 8%. The primary goal of cleft palate surgery is the establishment of a normal velopharyngeal valving system that separates the oral and nasal cavities during speech. By incorporating mirror-image Z-plasty incisions of the oral and nasal mucosa, Furlow's method lengthens the soft palate while preventing longitudinal scar contracture. Optimization of the management of velopharyngeal insufficiency in affected patients will ultimately require the completion of carefully designed, well-controlled prospective trials.