Hox proteins are transcriptional regulators that specify segmental identity along the anteroposterior axis of multicellular animals. In Drosophila, Hox proteins bind to DNA in association with the Extradenticle (Exd) and Homothorax (Hth) co-factors. The Hox DNA-binding selectivity model proposes that distinct Hox/Exd/Hth complexes select different consensus DNA-binding sites to initiate different developmental programs. On p. 1591,Ebner and colleagues question this model. By screening the Drosophilagenome for the consensus Lab/Exd/Hth-binding sequence, the authors have discovered a new target gene regulated by the Hox protein Labial (Lab). Surprisingly, the regulation of this gene by Lab does not depend on the Lab/Exd-binding consensus site but on a strongly divergent sequence. The researchers conclude that more complexity needs to be built into the Hox DNA-binding selectivity model to accommodate their findings. On p. 1567, Hersh and Carroll consider how Hox genes regulate development from an evolutionary point of view. The researchers identify the knot gene as a direct target of the Hox protein Ultrabithorax (Ubx) in the developing Drosophilahaltere and find that the minimal element for knot repression by Ubx is not conserved between Drosophila species. They conclude that Hox cis-regulatory regions, the evolutionary selection of which underlies how Hox proteins direct the production of different metazoan body forms, are more diffuse and larger than previously thought.