The relocalisation of gene loci outside chromosome territories and chromatin decondensation are generally regarded as linked facets of gene activation. Now, however, Wendy Bickmore and co-workers reveal that these processes can occur separately during activation of the Hoxd gene cluster (see p. 909). The researchers analysed the nuclear organisation of the mouse Hoxd cluster in differentiating embryonic stem (ES) cells and embryonic day 9.5 mouse embryos. The Hoxd cluster, they report, like the Hoxb cluster, looped out from its chromosome territory and unfolded after its activation in ES cells and in the embryonic tailbud. But, in the limb bud (another site of Hoxd activation), the chromatin unfolded without looping out. Furthermore, during ES cell differentiation, parts of the Hoxd cluster looped out before their chromatin visibly decondensed. Thus, although the chromosome remodelling mechanisms that underlie Hox gene activation predate the duplication of mammalian Hox loci,the exact mode of regulation of the Hoxd cluster depends on its developmental context.