Essential proteins called histones encase and assemble DNA into structural elements referred to as nucleosomes. These have a crucial role in regulating the expression of genes and conserving the integrity of the genome. Different post-translational modifications such as methylation, ubiquitination, phosphorylation, and acetylation govern the functions of histones. In the quest for disease treatment targets, histone-modifying enzymes, which alter numerous histone codes, have garnered much attention. Histone modifications are regulated by several enzymes, including histone deacetylases (HDACs), histone demethylases (HDMs), histone methyltransferases (HMTs), and histone acetyltransferases (HATs). To prevent and treat diseases, it is crucial to have a comprehensive understanding of how histone post-translational modifications (PTMs) affect cell life activities. In addition to contributing to chromatin structure and transcriptional activity, these enzymes dynamically interact with histone proteins to modulate several cellular functions like differentiation and development. This book chapter deals with the fundamental aspects of histone family proteins, enzymes that interact with the histones for modifications, and the aftereffects of histone modifications in health and disease. We also discuss the potential impacts of histone modification enzymes as therapeutic targets in translational research. Enhancing knowledge of the biological mechanisms that drive histone modification and binding helps in the control of gene expression and in designing novel treatment approaches.