During gastrulation, Hox genes are activated in a timesequence that follows the order of the genes along their clusters. This property, which is observed in all animals that develop following a progressive rostral-to-caudal morphogenesis, is associated with changes in the chromatin structure and epigenetic profiles of Hox clusters, suggesting a process at least partly based on sequential gene accessibility. Here, we discuss recent work on this issue, as well as a possible mechanism based on the surprising conservation in both the distribution and orientation of CTCF sites inside vertebrate Hox clusters.