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Summary Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from epigenetic silencing of the X-linked FMR1 gene by a CGG expansion in its 5′-untranslated region. Taking advantage of a large set of FXS-affected human embryonic stem cell (HESC) lines and isogenic subclones derived from them, we show that FMR1 hypermethylation commonly occurs in the undifferentiated state (six of nine lines, ranging from 24% to 65%). In addition, we demonstrate that hypermethylation is tightly linked with FMR1 transcriptional inactivation in undifferentiated cells, coincides with loss of H3K4me2 and gain of H3K9me3, and is unrelated to CTCF binding. Taken together, these results demonstrate that FMR1 epigenetic gene silencing takes place in FXS HESCs and clearly highlights the importance of examining multiple cell lines when investigating FXS and most likely other epigenetically regulated diseases., Highlights • FMR1 epigenetic gene silencing commonly occurs in the undifferentiated FXS cells • FXS HESCs are heterogeneous for repeat size and methylation levels • This study underscores the importance of multiple HESC lines in disease modeling, Fragile X syndrome (FXS) results from epigenetic silencing of the X-linked FMR1 gene. Using a large set of fragile X-affected human embryonic stem cell lines, Eiges and colleagues show that FMR1 epigenetic gene inactivation commonly occurs prior to embryonic tissue differentiation. This study underscores the importance of examining multiple cell lines in disease modeling, especially in epigenetically regulated disorders like FXS.