The article reviews the emerging mechanisms of long-range control of gene expression and the disruptions that can lead to diseases. It highlights the complex machinery required for transcriptional control, including enhancers and repressors that can reside in introns or up- and downstream of the transcription unit. The article discusses how chromosomal rearrangements can disrupt these regulatory elements, leading to disease. It provides examples of specific genes and diseases, such as aniridia caused by disruptions in the PAX6 gene, and TWIST-related developmental disorders. The article also explores the role of chromatin structure and histone modifications in regulating gene expression. It emphasizes the importance of understanding long-range control in disease mechanisms and the potential for novel therapeutic approaches.The article reviews the emerging mechanisms of long-range control of gene expression and the disruptions that can lead to diseases. It highlights the complex machinery required for transcriptional control, including enhancers and repressors that can reside in introns or up- and downstream of the transcription unit. The article discusses how chromosomal rearrangements can disrupt these regulatory elements, leading to disease. It provides examples of specific genes and diseases, such as aniridia caused by disruptions in the PAX6 gene, and TWIST-related developmental disorders. The article also explores the role of chromatin structure and histone modifications in regulating gene expression. It emphasizes the importance of understanding long-range control in disease mechanisms and the potential for novel therapeutic approaches.