Intellectual disability is the impairment of cognitive, linguistic, motor and social skills that contribute to the global level of intelligence that occurs in the pediatric age, and now comprises also the term “mental retardation” used in the past to describe the same impairments under 5 years of age. Intellectual disability involves 3% of the general population, also due to a genetic cause including chromosome aberrations to account for the 3–28% of intellectual disability. Between people with intellectual disabilities, the cause of the disorders was identified as a single gene disorder up to 12%, as multifactorial disorders up to 4%, and as genetic disorders up to 8.5%. Children affected by a malformation syndrome associated with mental retardation or intellectual disability represent a care challenge for the pediatrician. The presence of a multidisciplinary team is essential to manage the patient, trying to control the complications of the syndrome for promoting the correct psychophysical development. This encourages continuous follow-up of these children since the pediatrician is essential both in the clinical management of the syndrome and in facilitating the social integration of these children.