AbstractThe human X chromosome harbors only 4% of our genes but over 20% of loci associated with intellectual disability. Because they inherit only one X-chromosome, males are more frequently affected by X-linked neurodevelopmental genetic disorders. Despite inheriting two X-chromosomes, however, females can also be affected because X-chromosome inactivation (XCI) enables only one of two X chromosomes to be expressed per cell. Notable examples include Rett, CDKL5, and Fragile X syndromes. For these disorders, disease-specific treatments have remained elusive. In female subjects, a cure may be found within their own cells, as every sick cell carries a healthy copy of the affected gene on the inactive X (Xi). Selective Xi-reactivation may therefore be a viable approach that would address the root cause of various X-linked disorders. We will discuss current approaches to reactivate the silent MECP2 allele.