The evolution of vertebrate genomes was accompanied by an astounding increase in the complexity of their regulatory modalities. Genetic redundancy resulting from large-scale genome duplications at the base of the chordate tree was repeatedly exploited by the functional redeployment of paralogous genes via innovations in their regulatory circuits. As a paradigm of such regulatory evolution, we have extensively studied those control mechanisms at work in-cis over vertebrate Hox gene clusters. Here, we review the portfolio of genetic strategies that have been developed to tackle the intricate relationship between genomic topography and the transcriptional activities in this gene family, and we describe some of the mechanistic insights we gained by using the HoxD cluster as an example. We discuss the high heuristic value of this system in our general understanding of how changes in transcriptional regulation can diversify gene function and thereby fuel morphological evolution.