This review explores the emerging role of novel histone post-translational modifications (HPTMs) in various diseases and their potential as therapeutic targets. It defines nine novel HPTMs: lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butryrylation, 2-hydroxyisobutyrylation, and 2-hydroxybutryrylation. The review details the modification processes, their roles in transcription, replication, DNA repair, metabolism, and chromatin structure, as well as their involvement in disease development and progression. It also discusses the clinical applications of these HPTMs as therapeutic targets and potential biomarkers. Additionally, the review covers the development of novel HPTM inhibitors and their strategies in treating multiple diseases, highlighting future prospects and challenges. The historical context of epigenetics and the evolution of HPTM research are also discussed, emphasizing the dynamic nature of these modifications and their significance in cellular physiology and pathology.This review explores the emerging role of novel histone post-translational modifications (HPTMs) in various diseases and their potential as therapeutic targets. It defines nine novel HPTMs: lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butryrylation, 2-hydroxyisobutyrylation, and 2-hydroxybutryrylation. The review details the modification processes, their roles in transcription, replication, DNA repair, metabolism, and chromatin structure, as well as their involvement in disease development and progression. It also discusses the clinical applications of these HPTMs as therapeutic targets and potential biomarkers. Additionally, the review covers the development of novel HPTM inhibitors and their strategies in treating multiple diseases, highlighting future prospects and challenges. The historical context of epigenetics and the evolution of HPTM research are also discussed, emphasizing the dynamic nature of these modifications and their significance in cellular physiology and pathology.