Mental retardation occurs in more than 1% of the child population. A cause can be found in almost 80% of individuals with severe mental retardation, but in fewer than 40% of those with mild mental retardation. A work-up is indicated in all cases of mental retardation. A medical doctor with specific training in the field is needed to make “decision-tree diagnosis” and to suggest the most appropriate physical investigations in each case. This paper provides practical guidelines for diagnosis and work-up both in severe and mild mental retardation.