The mammalian genome is organized into a structure of DNA and proteins known as chromatin. In general, chromatin presents a barrier to gene expression that is regulated by several pathways, namely by the incorporation of histone variants into the nucleosome. In yeast, H2A.Z is an H2A histone variant that is incorporated into nucleosomes as an H2A.Z/H2B dimer by the Swr1 complex and by the SRCAP and p400/Tip60 complexes in mammalian cells. H2A.Z has been associated with the poising of genes for transcriptional activation in the yeast model system, and is essential for development in higher eukaryotes. Recent studies in our laboratory have demonstrated a p400-dependent deposition of H2A.Z at the promoter of p21WAF1/CIP1, a consequence that prevents the activation of the gene by p53, thereby inhibiting p53-dependent replicative senescence, a form of cell-cycle arrest crucial in the prevention of carcinogenic transformation of cells. Moreover, H2A.Z is overexpressed in several different types of cancers, and its overexpression has been associated functionally with the proliferation state of cells. Therefore, we suggest that H2A.Z is an important regulator of gene expression, and its deregulation may lead to the increased proliferation of mammalian cells.