Epigenetic mechanisms including the post-translational modifications of histones, incorporation of histonevariants and DNA methylation have been suggested to play an important role in genome plasticity by allowingthe cellular environment to define gene expression and the phenotype of an organism. Studies over the pastdecade have elucidated how these epigenetic mechanisms are significant in orchestrating various biologicalprocesses and contribute to different pathophysiological states. However, the role of histone isoforms and theirimpact on different phenotypes and physiological processes associated with diseases are not fully clear. Thisreview is focussed on the recent advances in our understanding of the complexity of eukaryotic H2A isoformsand their roles in defining nucleosome organization. We elaborate on their potential roles in genomic complexityand regulation of gene expression, and thereby on their overall contribution towards cellular phenotypeand development of diseases.