Hox genes are the homologues of the homeobox‐containing genes in the homeotic complex (HOM‐C) of the fruit fly Drosophila and encode transcription factors that play crucial roles in determining positional identity along the anterior–posterior body axis during animal development. Their expansion and duplication during metazoan evolution suggests that they have played a major role in generating animal diversity. In the protostomes, Hox genes are organised into a single cluster of genes that in some phyla has undergone gene loss and in others has become dispersed. On the contrary, cluster integrity is generally maintained in the deuterostomes, and during chordate evolution the single deuterostome cluster has undergone internal expansion as well as whole cluster duplications, generating animals with four or more clusters. Whereas these expansions and duplications are correlated with an increase in animal diversity, the main mechanisms driving metazoan evolution from a Hox perspective probably involve alterations in cis‐regulatory sequences of Hox genes and, to a lesser extent, changes in their coding sequences.

Key Concepts:

• The prototype Hox gene potentially evolved from an ancestral NK homeobox gene very early in metazoan evolution.
  
• Tandem and genome‐wide duplications generated the prototypical vertebrate Hox clusters.
  
• Hox genes encode transcription factors that may have originally patterned bilaterian's evolving nervous system; however, as body organisation became more complicated and cells became more interdependent, Hox genes’ function may have co‐evolved with the function of other HB‐containing genes to jointly specify positional information in the derivatives of all three germ layers.
  
• The clustering of Hox genes appears to be necessary for animals that use signalling pathways during development. This supports the presence of global control mechanisms that regulate all or a subset of genes within the cluster.
  
• Organisms in which cells are primarily determined in early embryogenesis and develop autonomously begin to lose Hox cluster integrity.
  
• The major morphological diversity in vertebrate lineages does not appear to be causally related to changes in the number or complement of the Hox genes. Therefore, Hox input into morphological diversity is likely to occur through altered cis‐regulation and/or downstream targets of Hox genes.
  
• As the genome sequence of more species becomes available, the molecular phylogenetics of Hox cluster evolution will become clearer with an emphasis in understanding the evolution of the regulatory modules that partition Hox expression domains.