The Drosophila central nervous system (CNS) is a key model for investigating brain development. The larval CNS is populated by neural stem cells, known as neuroblasts (NBs), that give rise to the majority of neurons in the adult brain. Although most NBs are type I (NBI), there is also a rare subpopulation of type II (NBII) neuroblasts. During NB differentiation, stem cell genes are silenced and lineage-specific genes must be activated. However, the dynamic modifications of histones have not been well studied in vivo. Now, Jürgen Knoblich and colleagues use a FACS-based ChIP-seq method to profile active and repressive chromatin states in different cell types isolated from the larval brain. They reveal that silencing of stem cell identity genes are regulated, not by gaining repressive histone marks, but through the loss of activating histone modifications. In addition, the authors use NB tumours (normalised against healthy NBI counterparts) to profile the rare NBII lineage. The researchers identify new genes specific to NBII cells and demonstrate a role for the Polycomb complex in providing repressive modifications that favour NBII differentiation. Together, these datasets provide a valuable resource of changing histone modifications in neuronal lineages.