This review explores the intersection of novel histone modifications (HPTMs) and diseases, highlighting their roles in gene expression, metabolism, chromatin structure, and disease progression. Nine novel HPTMs—lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, and 2-hydroxybutyrylation—are discussed in detail. These modifications influence transcription, replication, DNA repair, and chromatin dynamics, and are implicated in various diseases, including cancer, cardiovascular diseases, and psychiatric disorders. The review outlines the mechanisms of these modifications, their clinical relevance as therapeutic targets and biomarkers, and emerging strategies for their inhibition. It also introduces novel epigenetic research techniques and their applications in HPTM studies. The article emphasizes the dynamic and complex nature of HPTMs, their regulatory roles in cellular metabolism and gene expression, and their potential for therapeutic intervention. The review underscores the importance of understanding these modifications in advancing epigenetic research and developing targeted therapies for diseases.This review explores the intersection of novel histone modifications (HPTMs) and diseases, highlighting their roles in gene expression, metabolism, chromatin structure, and disease progression. Nine novel HPTMs—lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, and 2-hydroxybutyrylation—are discussed in detail. These modifications influence transcription, replication, DNA repair, and chromatin dynamics, and are implicated in various diseases, including cancer, cardiovascular diseases, and psychiatric disorders. The review outlines the mechanisms of these modifications, their clinical relevance as therapeutic targets and biomarkers, and emerging strategies for their inhibition. It also introduces novel epigenetic research techniques and their applications in HPTM studies. The article emphasizes the dynamic and complex nature of HPTMs, their regulatory roles in cellular metabolism and gene expression, and their potential for therapeutic intervention. The review underscores the importance of understanding these modifications in advancing epigenetic research and developing targeted therapies for diseases.