Methyl-CpG binding protein 2 (MeCP2), a nuclear protein highly expressed in neurons, was identified because of its ability to bind methylated DNA. In association with the transcriptional corepressor proteins Sin3a and histone deacetylases, it represses gene transcription. However, it has since become clear that MeCP2 is a multifunctional protein involved not only in transcriptional silencing but also in transcriptional activation, chromatin remodeling, and RNA splicing. Especially, its involvement in the X-linked neurologic disorder Rett syndrome emphasizes the importance of MeCP2 for normal development and maturation of the central nervous system. A number of animal models with complete or partial lack of MeCP2 functions have been generated to correlate the clinical phenotype of Rett syndrome, and studies involving different mutations of MeCP2 have shown similar effects. Animal model studies have further demonstrated that even the loss of a specific phosphorylation site of MeCP2 (S80, S421, and S424) disturbs normal maturation of the mammalian brain. This review covers recent findings regarding MeCP2 functions and its regulation by posttranslational modification, particularly MeCP2 phosphorylation and its effects on mammalian brain maturation, learning, and plasticity.