It is now well established that cells modify chromatin to set transcriptionally active or inactive regions. Such control of chromatin structure is essential for proper development of organisms. In addition to the growing number of histone post-translational modifications, cells can exchange canonical histones with different variants that can directly or indirectly change chromatin structure. Moreover, enzymatic complexes that can exchange specific histone variants within the nucleosome have now been identified. One such variant, H2A.Z, has recently been the focus of many studies. H2A.Z is highly conserved in evolution and has many different functions, while defining both active and inactive chromatin in different contexts. Advanced molecular techniques, such as genome-wide binding assays (chromatin immunoprecipitation on chip) have recently given researchers many clues as to how H2A.Z is targeted to chromatin and how it affects nuclear functions. We wish to review the recent literature and summarize our understanding of the mechanisms and functions of H2A.Z.