Complementary transcriptional and epigenetic regulatory factors (e.g., histone and chromatin modifying enzymes and non-coding RNAs) regulate genes responsible for mediating neural stem cell maintenance and lineage restriction, neuronal and glial lineage specification, and progressive stages of lineage maturation. However, an overall understanding of the mechanisms that sense and integrate developmental signals at the genomic level and control cell type-specific gene network deployment has not emerged. REST and CoREST are central players in the transcriptional and epigenetic regulatory circuitry that is responsible for modulating neural genes, and they have been implicated in establishing cell identity and function, both within the nervous system and beyond it. Herein, we discuss the emerging context-specific roles of REST and CoREST and highlight our recent studies aimed at elucidating their neural developmental cell type- and stage-specific actions. These observations support the conclusion that REST and CoREST act as master regulators of key neural cell fate decisions.