Simple SummaryHistone deacetylases (HDACs) are epigenetic regulators that influence chromatin structure and gene transcription, but also the function of non-histone targets like chaperones and proteins participating in the DNA damage response. Histone modifications are implicated in cancer and HDAC inhibitors (HDACis) can be useful to treat hematological malignancies, including leukemia, B-cell lymphoma, virus-associated tumors, and multiple myeloma. Several HDACis were approved for clinical use and others are showing promising results, especially as adjuvants to conventional treatments. In addition to synthetic inhibitors, this work discusses the potential of phytocompounds, such as chrysin and oleacein as well as marine-derived agents, such as halenaquinone and xestoquinone, as therapeutic agents against hematological cancers.AbstractHistone deacetylases (HDACs) and histone acetyltransferases (HATs) are enzymes that remove or add acetyl groups to lysine residues of histones, respectively. Histone deacetylation causes DNA to more snugly encircle histones and decreases gene expression, whereas acetylation has the opposite effect. Through these small alterations in chemical structure, HATs and HDACs regulate DNA expression. Recent research indicates histone deacetylase inhibitors (HDACis) may be used to treat malignancies, including leukemia, B-cell lymphoma, virus-associated tumors, and multiple myeloma. These data suggest that HDACis may boost the production of immune-related molecules, resulting in the growth of CD8-positive T-cells and the recognition of nonreactive tumor cells by the immune system, thereby diminishing tumor immunity. The argument for employing epigenetic drugs in the treatment of acute myeloid leukemia (AML) patients is supported by evidence that both epigenetic changes and mutations in the epigenetic machinery contribute to AML etiology. Although hypomethylating drugs have been licensed for use in AML, additional epigenetic inhibitors, such as HDACis, are now being tested in humans. Preclinical studies evaluating the efficacy of HDACis against AML have shown the ability of specific agents, such as anobinostat, vorinostat, and tricostatin A, to induce growth arrest, apoptosis, autophagy and cell death. However, these inhibitors do not seem to be successful as monotherapies, but instead achieve results when used in conjunction with other medications. In this article, we discuss the mounting evidence that HDACis promote extensive histone acetylation, as well as substantial increases in reactive oxygen species and DNA damage in hematological malignant cells. We also evaluate the potential of various natural product-based HDACis as therapeutic agents to combat hematological malignancies.