The history of globin research is marked by a series of contributions seminal to our understanding of the genome, its function, and its relation to disease. For example, based on studies on hemoglobinopathies, it was understood that gene expression can be under the control of DNA elements that locate away from the genes on the linear chromosome template. Recent technological developments have allowed the demonstration that these regulatory DNA elements communicate with the genes through physical interaction, which loops out the intervening chromatin fiber. Subsequent studies showed that the spatial organization of the β-globin locus dynamically changes in relation to differences in gene expression. Moreover, it was shown that the β-globin locus adopts a different position in the nucleus during development and erythroid maturation. Here, we discuss the most recent insight into the three-dimensional organization of gene expression.