For many years, histones were considered to be passive structural components of eukaryotic chromatin. Experimental evidence that has accumulated during the past few years indicates that in addition to their structural role, histones play a very important functional role and that they can operate as epigenetic markers. This notion has rekindled the interest in histone variants and their participation in the processes of chromatin activation and inactivation. Recent papers have focused their attention on histone H2A variants. The variants of this overlooked histone participate in many biological processes ranging from transcriptional activation to DNA repair, meiosis, and apoptosis. A nucleosome containing at least one of these variants has been crystallized and biophysically characterized in solution. From all these results, a new concept has started to emerge, which supports the notion that the functional roles of H2A variants are exerted through alterations in chromatin stability and folding that result from the structural variation at the carboxyl-terminal end of this histone.