Causes of mental retardation that affects 1-2% of general population are numerous and heterogeneous and include genetic and environmental factors. Improvement of diagnostic techniques and progress made in mapping genes associated with specific mental retardation syndromes provide the possibility to make precise diagnosis in a proportion of mentally retarded individuals. The present study reviews the current diagnostic possibilities, highlights the problems involved in the diagnosis of mental retardation, providing practical guidelines for rational diagnostic approach and work up in individuals with mental retardation. Diagnosis is highly dependent on a detailed and comprehensive family and personal history, careful physical examination and long-term follow up of the children with developmental delay. Referral to specialised genetic units, where extensive evaluation based on rational selection of the specific investigations is possible, yields best diagnostic results.