The human beta-globin locus is a complex genetic system widely used for analysis 
of eukaryotic gene expression. The locus consists of five functional beta-like 
globin genes, epsilon, (G)gamma, (A)gamma, delta, and beta, arrayed on the 
chromosome in the order that they are expressed during ontogeny. Globin gene 
expression is regulated, in part, by the locus control region, which physically 
consists of five DNaseI-hypersensitive sites located 6-22 Kb upstream of the 
epsilon -globin gene. During ontogeny two switches occur in beta-globin gene 
expression that reflect the changing oxygen requirements of the fetus. The first 
switch from embryonic epsilon - to fetal gamma-globin occurs at six weeks of 
gestation. The second switch from gamma- to adult delta- and beta-globin occurs 
shortly after birth. Throughout the locus, cis-acting elements exist that are 
dynamically bound by trans-acting proteins, including transcription factors, 
co-activators, repressors, and chromatin modifiers. Discovery of novel 
erythroid-specific transcription factors and a role for chromatin structure in 
gene expression have enhanced our understanding of the mechanism of globin gene 
switching. However, the hierarchy of events regulating gene expression during 
development, from extracellular signaling to transcriptional activation or 
repression, is complex. In this review we attempt to unify the current knowledge 
regarding the interplay of cis-acting elements, transcription factors, and 
chromatin modifiers into a comprehensive overview of globin gene switching.