This review discusses the role of histone deacetylases (HDACs) in cancer development and the therapeutic potential of HDAC inhibitors (HDACi) in cancer treatment. HDACs play a crucial role in cancer by modulating gene transcription, chromatin remodeling, and nuclear architecture through the removal of acetyl groups from histone tails. Abnormal alterations in histone acetylation, such as global loss of acetylation at lysine 16 and trimethylation at lysine 20 of histone H4, are common in human cancer. Additionally, aberrant expression of HDACs is frequently observed in various cancers, contributing to the overall principle of targeting HDACs for cancer therapy. HDACs are involved in multiple stages of cancer, including cell cycle regulation, apoptosis, DNA damage response, metastasis, angiogenesis, and autophagy. HDAC inhibition can arrest the cell cycle at the G1/S or G2/M phase, induce apoptosis through the extrinsic and intrinsic pathways, and disrupt DNA damage repair processes. HDACs also regulate metastasis by influencing epithelial-to-mesenchymal transition (EMT) and angiogenesis. The antiangiogenic activity of HDAC inhibition is associated with decreased expression of proangiogenic genes. The availability of HDACi has accelerated our understanding of HDAC functions and presented a promising new class of compounds for cancer treatment. Nonselective HDACi, such as vorinostat, belinostat, and panobinostat, have been widely studied and approved for the treatment of cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphomas (PTCL), and multiple myeloma. Selective HDACi, including class I HDACi (romidepsin and entinostat) and HDAC6 inhibitors (ricolinstat), have shown promise in preclinical studies. Multipharmacological HDACi, such as CUDC-101 and CUDC-907, are also under development. The clinical landscape of HDACi in cancer therapy has been largely restricted to hematological malignancies, with positive responses in leukemias, lymphomas, and multiple myeloma. However, their efficacy in solid tumors is disappointing when used as monotherapy. Side effects and toxicity are common obstacles in the use of HDACi, and further research is needed to develop selective inhibitors and explore combination therapies to improve their therapeutic outcomes.This review discusses the role of histone deacetylases (HDACs) in cancer development and the therapeutic potential of HDAC inhibitors (HDACi) in cancer treatment. HDACs play a crucial role in cancer by modulating gene transcription, chromatin remodeling, and nuclear architecture through the removal of acetyl groups from histone tails. Abnormal alterations in histone acetylation, such as global loss of acetylation at lysine 16 and trimethylation at lysine 20 of histone H4, are common in human cancer. Additionally, aberrant expression of HDACs is frequently observed in various cancers, contributing to the overall principle of targeting HDACs for cancer therapy. HDACs are involved in multiple stages of cancer, including cell cycle regulation, apoptosis, DNA damage response, metastasis, angiogenesis, and autophagy. HDAC inhibition can arrest the cell cycle at the G1/S or G2/M phase, induce apoptosis through the extrinsic and intrinsic pathways, and disrupt DNA damage repair processes. HDACs also regulate metastasis by influencing epithelial-to-mesenchymal transition (EMT) and angiogenesis. The antiangiogenic activity of HDAC inhibition is associated with decreased expression of proangiogenic genes. The availability of HDACi has accelerated our understanding of HDAC functions and presented a promising new class of compounds for cancer treatment. Nonselective HDACi, such as vorinostat, belinostat, and panobinostat, have been widely studied and approved for the treatment of cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphomas (PTCL), and multiple myeloma. Selective HDACi, including class I HDACi (romidepsin and entinostat) and HDAC6 inhibitors (ricolinstat), have shown promise in preclinical studies. Multipharmacological HDACi, such as CUDC-101 and CUDC-907, are also under development. The clinical landscape of HDACi in cancer therapy has been largely restricted to hematological malignancies, with positive responses in leukemias, lymphomas, and multiple myeloma. However, their efficacy in solid tumors is disappointing when used as monotherapy. Side effects and toxicity are common obstacles in the use of HDACi, and further research is needed to develop selective inhibitors and explore combination therapies to improve their therapeutic outcomes.