Regulatory T cells (T) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4Forkhead box protein3 (CD4FOXP3), these cells are a subset of CD4 T lymphocytes and can originate from the thymus (tT) or from the periphery (pT). The malfunction of CD4 T is associated with autoimmune responses such as rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), inflammatory bowel diseases (IBD), psoriasis, systemic lupus erythematosus (SLE), and transplant rejection. Recent evidence supports an opposed role in sepsis. Therefore, maintaining functional T is considered as a therapy regimen to prevent autoimmunity and allograft rejection, whereas blocking T differentiation might be favorable in sepsis patients. It has been shown that T can be generated from conventional naïve T cells, called iT, due to their induced differentiation. Moreover, T can be effectively expanded in vitro based on blood-derived tT. Taking into consideration that the suppressive role of T has been mainly attributed to the expression and function of the transcription factor Foxp3, modulating its expression and binding to the promoter regions of target genes by altering the chromatin histone acetylation state may turn out beneficial. Hence, we discuss the role of histone deacetylation inhibitors as epigenetic modulators of T in this review in detail.