The transition of a cell from one state to another involves large changes in the organization of its chromatin. Indeed, it has become increasingly clear that modifications of the chromatin are the molecular basis of an epigenetic memory that defines cellular identity. Histone variants are likely candidates to contribute to epigenetic regulations. Genome-wide profiling of the unusual macroH2A histone variants and the identification of interacting proteins provided important clues to their molecular and physiological function.