Hundreds of specific causes of mental retardation have been identified. Many of these are multiple congenital anomaly/mental retardation syndromes. These include any condition characterized by mental retardation as well as multiple birth defects. However, in nearly a quarter of all cases, the cause of mental retardation is not known.

Any brain injury or developmental problem in the brain may result in mental retardation. Such problems may occur before, during or after birth. Prenatal causes of mental retardation include genetic disorders (e.g., Down syndrome, Fragile X syndrome, phenylketonuria), infections in the mother or fetus during pregnancy (e.g., rubella, cytomegalovirus, chickenpox) and exposure to various teratogens during pregnancy. A teratogen is any chemical, substance or other harmful agent that may cause birth defects to a developing fetus. These include certain medications, alcohol, recreational drugs, smoking, and radiation. Prenatal conditions, especially chromosomal disorders or other genetic conditions, are by far the most common cause of mental retardation. Asphyxia (lack of oxygen to the brain) and other problems during delivery may also cause mental retardation. However, problems during delivery only rarely result in mental retardation.

Although the development of mental retardation in infancy or childhood is rare, it can occur due to several potential causes. Serious infections in infancy (e.g., meningitis, whooping cough, measles) and serious head injuries (e.g., shaken baby syndrome, head trauma) are important postnatal causes. Lead or mercury poisoning, suffocation, stroke and extreme malnutrition can also cause mental retardation. Infants who are born premature or with a low birthweight may also have an increased risk. There also seems to be an association between the age of the mother during the pregnancy and the risk of mental retardation in the child.