In the central nervous system, epigenetic processes are involved in a multitude of brain functions ranging from the development and differentiation of the nervous system through to higher‐order cognitive processes such as learning and memory. This review summarises the current state of the art for the proteomic analysis of the epigenetic regulation of gene expression, in particular the PTM of histones, in the brain and cellular model systems. It describes the MS technologies that have helped the identification and analysis of histones, histone variants and PTMs in the brain. Strategies for the isolation of histones that allow the qualitative analysis of PTMs and their combinatorial patterns are introduced, methods for the relative and absolute quantification of histone PTMs are described, and future challenges are discussed.