The identification of an increasing number of posttranslationally modified residues within histone core domains is furthering our understanding of how nucleosome dynamics are regulated. In this review, we first discuss how the targeting of specific histone H3 core residues can directly influence the nucleosome structure and then apply this knowledge to provide functional reasoning for their localization to distinct genomic regions. While we focus mainly on transcriptional implications, the principles discussed in this review can also be applied to their roles in other cellular processes. Finally, we highlight some examples of how aberrant modifications of core histone residues can facilitate the pathogenesis of some diseases.