The article by Kevin Struhl reviews the mechanisms by which histone acetylation and deacetylation regulate transcription in eukaryotic cells. Over 30 years ago, it was proposed that histone acetylation is associated with transcriptional activity, and subsequent studies confirmed that acetylated core histones preferentially associate with transcriptionally active chromatin. Acetylation of histone tails neutralizes their positive charge, reducing their affinity for DNA and altering nucleosomal conformation, which can increase the accessibility of transcriptional regulatory proteins to chromatin templates. However, the underlying molecular mechanisms and the causal relationship between histone acetylation and transcriptional activity were not well understood until recently. Recent advances have identified proteins with intrinsic histone acetylase and deacetylase activity, many of which are also involved in transcriptional regulation. These discoveries have shifted the paradigm, showing that chromatin structure and modification are not independent of transcriptional initiation but instead serve as critical links between chromatin structure and transcriptional output. The review discusses the diverse functions of histone acetylases and deacetylases, their specificities, and their roles in gene expression. It also explores models for how these enzymes selectively affect gene expression, including untargeted, generally targeted, and gene-specific targeting models. The article highlights the importance of understanding the molecular mechanisms by which histone acetylation and deacetylation affect transcriptional activity, particularly in vivo, and the potential implications for long-range chromatin structures and gene regulation.The article by Kevin Struhl reviews the mechanisms by which histone acetylation and deacetylation regulate transcription in eukaryotic cells. Over 30 years ago, it was proposed that histone acetylation is associated with transcriptional activity, and subsequent studies confirmed that acetylated core histones preferentially associate with transcriptionally active chromatin. Acetylation of histone tails neutralizes their positive charge, reducing their affinity for DNA and altering nucleosomal conformation, which can increase the accessibility of transcriptional regulatory proteins to chromatin templates. However, the underlying molecular mechanisms and the causal relationship between histone acetylation and transcriptional activity were not well understood until recently. Recent advances have identified proteins with intrinsic histone acetylase and deacetylase activity, many of which are also involved in transcriptional regulation. These discoveries have shifted the paradigm, showing that chromatin structure and modification are not independent of transcriptional initiation but instead serve as critical links between chromatin structure and transcriptional output. The review discusses the diverse functions of histone acetylases and deacetylases, their specificities, and their roles in gene expression. It also explores models for how these enzymes selectively affect gene expression, including untargeted, generally targeted, and gene-specific targeting models. The article highlights the importance of understanding the molecular mechanisms by which histone acetylation and deacetylation affect transcriptional activity, particularly in vivo, and the potential implications for long-range chromatin structures and gene regulation.