Histone variant are non-allelic forms of the conventional histones. They are expressed at very low levels compared to their conventional counterparts. All the conventional histones, except H4, have histone variants. Together with histone modifications and chromatin remodeling machines, the incorporation of histone variants into the nucleosome is one of the main strategies that the cell uses to regulate transcription, repair, chromosome assembly and segregation. The exact role of the histone variants in these processes is far from clear, but the emerging picture is that the presence of histone variants confers novel structural and functional properties of the nucleosome which affect the chromatin dynamics. In this article we will discuss the functional significance of histone variants on chromatin function and its link to disease manifestation