AbstractGene therapy for inborn errors of metabolism that cause mental retardation remains a major challenge to gene therapists. In general, such disorders can be divided into two categories: those in which the primary site of pathology resides outside of the central nervous system (CNS), leading to the accumulation of toxic compounds that cross the blood‐brain barrier and cause neurologic dysfunction, and those in which the primary site of pathology resides within the neurons of the CNS. We focus on the strategies and prospects for treating the latter group of diseases, which require delivery of therapeutic genes or gene products to the CNS. Both ex vivo and in vivo approaches can be used. Among the ex vivo strategies, transplanted, genetically corrected hematopoietic stem cells obtained from a patient can enter the CNS and establish microglia within the brain that then secrete therapeutic proteins. Alternatively, neural cells such as oligodendrocytes or astrocytes can be obtained by brain biopsy, genetically corrected in the laboratory using viral or nonviral vectors, then autologously transplanted back into patients for migration and secretion of the therapeutic gene products. Among the in vivo delivery techniques, direct stereotaxic injection of therapeutic gene constructs can be used to correct a metabolic abnormality in a specific region. Intracarotid injection of therapeutic genes coupled with transient disruption of the blood brain barrier could also be used to obtain global delivery. Various approaches to the treatment of inborn errors of metabolism with mental retardation can be envisioned. We discuss each of the major gene delivery systems and related therapeutic strategies. © 1995 Wiley‐Liss,