The epigenetic paradigm encompasses a vast network of factors that form the building blocks and regulatory core of the eukaryotic chromatin. Among the key determinants of epigenetic regulation, covalent chromatin modifications, including histone modifications and DNA methylation, histone variants, RNA modifications and non-coding RNA have been the most extensively characterized. The epigenetic machinery modulates DNA accessibility and the recruitment of DNA-binding factors, thus playing pivotal roles in nearly all chromatin-templated cellular processes, such as transcription, DNA replication, DNA damage repair, and chromatin organization. On the one hand, epigenetic factors wrap around the genomic DNA, serving as a mediator of gene-environment interactions, as well as a protective layer against external and internal stimuli, which ensures high-fidelity genetic duplication and DNA repair. On the other hand, chromatin represents a structural barrier that limits the exposure and accessibility of the genomic DNA to various protein complexes, which is precisely regulated to permit or restrict certain DNA-based transactions. Therefore, the dynamic and reversible nature of epigenetic modifications allows for a certain degree of phenotypic plasticity, while preserving genomic integrity.