Mental retardation is a group of cognitive disorders with a significant worldwide prevalence rate. This high rate, together with the considerable familial and societal burden resulting from these disorders, makes it an important focus for prevention and intervention. While the diseases associated with mental retardation are diverse, a significant number are linked with disruptions in epigenetic mechanisms, mainly due to loss-of-function mutations in genes that are key components of the epigenetic machinery. Additionally, several disorders classed as imprinting syndromes are associated with mental retardation. This review will discuss the epigenetic abnormalities associated with mental retardation, and will highlight their importance for diagnosis, treatment, and prevention of these disorders.