Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MeCP2. RTT is characterized by having apparently normal development until 6-18 months, when a progressive decline in motor and language functions begins and breathing abnormalities and seizures present. Here we present the first proteomic analysis in a RTT mouse model. Examining whole cortex tissue in symptomatic males (Mecp2Jae/y) and wild-type littermates, we have identified 465 proteins significantly altered. Pathway analysis identified biological pathways ubiquitous to multiple cell types as well as cell type specific pathways, underscoring the contributions of multiple central nervous system (CNS) cell populations to the disease pathogenesis.