While some aspects of vertebrate embryonic development are highly conserved, others are variable and determine the extraordinary morphological variability observed across species. Hox genes are likely candidates in shaping the body plan of organisms over the course of evolution, owing to their instrumental functions in the patterning of developing structures. Snakes, in particular, have a very elongated trunk and are limbless, representing one of the most extreme morphological adaptations in the vertebrate clade. In this study, we show that the evolution of the snake extreme body plan has been accompanied by major regulatory changes at the HoxD locus while respecting a very conserved global structural constraint.