The Rett syndrome (RTT) is a severe X-linked postnatal and progressive neurodevelopmental disorder striking mostly girls with a prevalence of ∼1/10,000 female live births. RTT clinical symptoms, starting at 6–18 months of age, include deceleration of head growth, loss of speech and purposeful hand movements, mental retardation, autistic features, anxiety, seizures as well as motor and respiratory abnormalities. RTT is caused by mutations in the gene coding for the methyl-CpG-binding protein 2 (MeCP2) (Amir et al., 1999). MeCP2 is a transcriptional repressor involved in chromatin remodeling as well as a modulator of RNA splicing. As a transcriptional repressor, MeCP2 binds preferentially to methyl-CpG dinucleotides adjacent to A/T-rich sequences and recruits the co-repressor Sin3 complex containing HDAC1 and HDAC2 or other co-repressor complexes (Bienvenu and Chelly, 2006; Chahrour and Zoghbi, 2007). Alternately, MeCP2 achieves chromatin compaction by binding to linker DNA and nucleosomes (Nikitina et al., 2007a,b). A vast array of mutations, deletions or rearrangements has been identified in the MECP2 gene. This genetic variability and the pattern of X chromosome inactivation leading to mosaic expression of the mutant gene give rise to RTT phenotypes with variable severity (Bienvenu and Chelly, 2006; Chahrour and Zoghbi, 2007). It was found that not only loss of MeCP2 function but also gain in MeCP2 dosage lead to RTT-like clinical symptoms (Moretti and Zoghbi, 2006). Although the MECP2 gene is ubiquitously expressed, high MeCP2 levels are specific to postnatal neuronal maturation, explaining why a deficiency in MeCP2 selectively causes neuronal symptoms and results in the defective dendritic branching and altered number of synapses observed in RTT brains (Lasalle, 2004). Studies with several mouse models for RTT confirmed that MeCP2 dysfunction selectively affects postnatal neuronal maturation, and MeCP2 is not a global transcriptional repressor of methylated genes as it was initially assumed. Thus, the identification of MeCP2 target genes has been a main goal among scientists studying RTT, particularly that reversibility of the disease has been demonstrated in RTT mouse models. Indeed, it was shown that reactivating the Mecp2 gene after the onset of disease in RTT mice models can rescue RTT phenotype at least partially (Giacometti et al., 2007; Guy et al., 2007; Jugloff et al., 2008). It is speculated that even in the absence of MeCP2, the epigenetic marks interpreted by MeCP2, are properly formed and following Mecp2 restoration, MeCP2 occupies its designated sites to recover the proper expression profiles in the affected neurons (Bird, 2008). The search for MeCP2 target genes has been complicated by conflicting results, and it seems that the answer to whether a gene is a target for regulation by MeCP2 varies with the cellular and developmental context (Chahrour and Zoghbi, 2007; Lasalle, 2007). One of the identified genes, BDNF coding for the brain-derived neurotrophic factor, has attracted a lot of attention because of its role in neuronal survival and synaptic changes that are basic to memory and learning. It was found that Bdnf expression, repressed by MeCP2, is induced upon neuronal activity-dependent phosphorylation of MeCP2 which results in its dissociation from the Bdnf promoter. It was shown that this phosphorylation event mediates the ability of MeCP2 to regulate dendritic patterning and spine morphogenesis as well as the activity-dependent induction of Bdnf transcription (Zhou et al., 2006). It is believed that MeCP2 role as regulator of the expression of genes such as BDNF is crucial in modulating synaptic function and plasticity. However, another unexpected twist in the understanding of MeCP2 role comes with recent studies suggesting that MeCP2 can serve both as a repressor and as an activator (Yasui et al., 2007; Chahrour et al., 2008). Indeed, in gene expression profiles of the hypothalamus in mice lacking/or overexpressing Mecp2, researchers have found that in 85% of cases MeCP2 acts as an activator (Chahrour et al., 2008). It was shown that MeCP2 is associated with the activating factor CREB1 (cAMP responsive element binding protein 1) at the promoter of an activated gene, but not a repressed gene. Moreover, promoter regions of genes activated by MeCP2 are enriched in undermethylated CpG islands (Chahrour et al., 2008). According to these studies, RTT would be mostly due to loss of transcriptional activation rather than loss of repression.