The histones H2A, H2B, H3 and H4 are very conserved basic proteins that wrap almost two turns of DNA to form the nucleosome core. Conventional histones can be replaced with histone variants that are found in all eukaryotic organisms. Together with other nucleosome modification pathways, histone variants participate in the functional specialization of chromatin. In this review, we focus on three major H2A histone variants: H2A.X, H2A.Z and macroH2A. Recent discoveries highlight their involvement in crucial events such as DNA repair and transcriptional regulation.