Rett syndrome, a pervasive X-linked neurodevelopmental disorder in young girls, is caused by loss-of-function mutations in the gene that encodes the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). Mecp2-knockout mice phenocopy the major symptoms found in human patients and have advanced our understanding of the function of MeCP2 and mechanism of Rett syndrome. To study the behavior of the MeCP2 protein in vivo, we have generated a knock-in reporter mouse model that expresses MeCP2-enhanced green fluorescent protein (EGFP) fusion protein instead of endogenous MeCP2. Here we show that expression of the fusion protein in the brain remarkably mirrors endogenous MeCP2 expression in all temporal and spatial aspects. This mouse model may be a valuable tool for studying Rett syndrome and for developing therapies.