: Sepsis has pro- and anti-inflammatory processes caused by infectious agents. Sepsis survivors have impaired immune response due to immunosuppression. Gene expression during the inflammatory process is guided by transcriptional access to chromatin, with post-translational changes made in histones that determine whether the loci of the inflammatory gene are active, balanced, or suppressed. For this, a review literature was performed in PubMed included 'sepsis' and 'epigenetic' and 'immunosuppression' terms until May 2020.: This review article explores the relationship between epigenetic mechanisms and the pathophysiology of sepsis. Epigenetic changes, vulnerable gene expression, and immunosuppression are related to inflammatory insults that can modify the dynamics of the central nervous system. Therefore, it is important to investigate the timing of these changes and their dynamics during the disease progression.: Epigenetic changes are associated with the main stages of sepsis, from the pathogen-host interaction to inflammation and immunosuppression. These changes are key regulators of gene expression during physiological and pathological conditions. Thus, epigenetic markers have significant prognostic and diagnostic potential in sepsis, and epigenetic changes can be explored in combination with therapeutic strategies in experimental models of the disease.