October 2014 Image In this review, Doug explains how much we learned over the last 30 years from studies on single loci, such as the α- and β-globin genes clusters. Early studies of these genes clusters have led to discover the general principles of mammalian gene regulation. More recently, advanced technologies in molecular biology combined with high-throughput sequencing have been used to map remote regulatory elements in the genome and have revealed that common principles of gene regulation are emerging. http://www.plosgenetics.org/doi/pgen.1004668