Mutations in methyl CpG binding protein 2 (MECP2) cause Rett syndrome, an X-linked neurological disorder with autistic features and developmental regression. Mutation of MECP2 causes widespread gene dysregulation, making the syndrome difficult to treat. Mecp2 mouse mutants provide an excellent animal model to identify molecules that are important for disease pathogenesis. Studies of the mouse model have shown that the symptoms can be reversed by introduction of Mecp2 and partially rescued by other factors, providing evidence that therapeutic intervention is possible in humans. MECP2 mutation impacts many biological pathways, but it is unclear which are relevant to symptom onset and progression. A modifier screen is a forward-genetic approach to find mutations that suppress or enhance a phenotype of interest, allowing the organism to reveal important pathways for morbidity. Here, random unbiased mutagenesis with N-ethyl-N-nitrosourea (ENU) was employed to isolate mutations that suppressed clinical signs and improved overall health in a Mecp2 mouse model. Strikingly, the lesions identified by whole exome sequencing and segregation in 46 suppressing lines reveal 32 candidate genes that lie in only four pathways. One modifying mutation showed that cholesterol synthesis was abnormal in Mecp2 mice, and revealed the importance of brain lipid homeostasis to neurological function. Subsequent data show that MECP2 is required to link a repressor complex that regulates lipid homeostasis to DNA. Because MECP2 is ubiquitously expressed, metabolic syndrome also develops in Mecp2 mice. Many of the suppressor mutations lie in the pathway that regulates lipid homeostasis, and metabolic modulators such as statin drugs improve health. Lipid homeostasis thus represents a potential new therapeutic target for Rett syndrome treatment. Altogether, our data suggest that multiple factors will be required to reverse disease entirely, requiring combination therapies. A similar genetic approach could be exploited to identify targetable pathways involved in other “untreatable” diseases, opening a new field for translational discovery.