Histone variant H2A.Z is essential in higher eukaryotes and has different functions in the cell. Several studies indicate that H2A.Z is found at specific loci in the genome such as regulatory-gene regions, where it poises genes for transcription. Itsdeposition creates chromatin regions with particular structural characteristics which could favor rapid transcription activation. This review focuses on the highly regulated mechanism of H2A.Z deposition in chromatin which is essential for genome integrity. Chaperones escort H2A.Z to large ATP-dependent chromatin remodeling enzymes which are responsible for its deposition/eviction. Over the last ten years, biochemical, genetic and genomic studies helped us understand the precise role of these complexes in this process. It hasbeen suggested that a cooperation occurs between histone acetyltransferase and chromatin remodeling activities to incorporate H2A.Z in chromatin. Its regulated deposition near centromeres and telomeres also shows its implication in chromosomal structure integrity and parallels a role in DNA damage response. Thedynamics of H2A.Z deposition/eviction at specific loci was shown to be critical for genome expression andmaintenance, thus cell fate. Altogether, recent findings reassert the importance of the regulated depositionof this histone variant. This article is part of a Special Issue entitled: Histone chaperones and Chromatin assembly.