Gene expression is regulated by complex coordinated processes, including chromatin remodeling, post-translational modifications of histones, and incorporation of non-allelic histone variants. The histone variant H2AZ constitutes only a few percents of the total H2A cellular pool (Ball et al., 1983; West and Bonner, 1980). However, H2AZ is essential in several multi-cellular organisms (Faast et al., 2001; Ren and Gorovsky, 2001; Ridgway et al., 2004; van Daal and Elgin, 1992) and required for normal proliferation in Schizosaccharomyces pombe and Saccharomyces cerevisiae (Carr et al., 1994; Santisteban et al., 2000). In mammalian cells, H2AZ is involved in embryonic stem (ES) cell biology (Faast et al., 2001; Creyghton et al., 2008). Recent reports define the importance of H2AZ and H2AZ-modifying enzymes in self-renewal of ES cells (Binda et al., 2013; Hu et al., 2013; Li et al., 2012). In addition, H2AZ is post-translationally modified by acetylation, SUMOylation, ubiquitination, and methylation of lysines (Binda et al., 2013). Herein, we summarize our perspective on the emergent role of H2AZ in the biology of ES cells, while bringing a particular emphasis on the functions of its post-translational modifications.