Patient-specific induced pluripotent stem (iPS) cells, generated from somatic cells of disease-affected individuals, hold a tremendous potential for studying disease mechanisms and for drug screening approaches using cell types previously not available (Yamanaka, 2008). Fragile-X (FX) syndrome belongs to the autism spectrum disorders, and is the most common cause of inherited mental retardation with the prevalence of 1/3600 (Crawford et al., 2001). It is nearly always caused by silencing of the FMR1 gene due to abnormal CGG repeat expansions in the 5′-UTR of the gene (Verkerk et al., 1991). Abnormal CGG repeat expansion of over 200 repeats leads to transcriptional silencing and CpG methylation of the gene 5′-UTR and the gene promoter (Sutcliffe et al., 1992). The silencing of the FMR1 gene and the heterochromatinization of the gene promoter were shown to be developmentally dependent (Eiges et al., 2007). In undifferentiated human FX embryonic stem cells (FX-ES cells) derived from affected blastocyst-stage embryos, FMR1 is expressed and gene silencing occurs only upon differentiation (Eiges et al., 2007). Recently, we have generated 11 FX-iPS cell lines from three different FX patients (Urbach et al., 2010). In FX-iPS cells, and contrary to FX-ES cells, the gene is transcriptionally silent both in the pluripotent and differentiated states (Urbach et al., 2010). The absence of FMR1 expression in FX-iPS cells is accompanied by DNA methylation and histone modifications indicative of heterochromatin in the gene promoter (Urbach et al., 2010). Although FX-iPS cells cannot recapitulate the developmentally dependent silencing of FMR1, they represent a unique genetic model system that harbors a completely silent FMR1 locus to study disease phenotypes, and for potential drug screening using the most suitable cells in the context of the disease and the affected individual.