In recent years there has been a growing appreciation for the importance of histone variants. The exchange of core histones for histone variants within the nucleosome has distinct and profound consequences within the cell and can change the chromatin architecture. MacroH2A variants are unique histone variants due to the presence of a 30kDa non-histone domain (macro domain) at their C-termini. MacroH2A variants are generally considered transcriptionally repressive in nature due to their association with forms of condensed chromatin such as the inactive X chromosome (Xi), senescence-associated heterochromatin foci (SAHF) and inactive genes. However, macroH2A variants may play additional regulatory roles in the cell. We have been studying macroH2A biology for a number of years and we identified some of the very first PTMs of macroH2A. We have demonstrated that macroH2A histone variants act as an epigenetic barrier when somatic cells are challenged to reprogram via transcription factor (TF)-mediated induced pluripotency. We further showed that macroH2A and its highly associated histone modification, H3K27me3, are enriched at a critical set of Utx (H3K27me3 demethylase) target genes whose expression is critical for the early stages of induced pluripotency. We continue to study the role of macroH2A as a barrier to iPS reprogramming and to tumorigenesis. Moreover, we aim to understand how macroH2A chromatin deposition is regulated and have previously reported a role for ATRX in this process.