Recent studies have uncovered a role for astrocytes in the pathophysiology of Rett syndrome, most cases of which are linked to mutations in methyl-CpG-binding protein 2 (MECP2). A new study shows that microglial dysfunction may also have an important role in this disorder. Transplantation of wild-type murine bone marrow into male Mecp2−/− mice that had undergone postnatal irradiation led to engraftment of MECP2-expressing microglia-like cells in the brain parenchyma and a cessation of disease progression. Moreover, mice in which MECP2 expression was restricted to myeloid cells, including microglia, showed a similar phenotype. Finally, pharmacological blockade of microglial phagocytic activity in these animals attenuated disease improvement.