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Fossil data suggest that limbs evolved from fish fins by sequential elaboration of their distal endoskeleton, giving rise to the autopod close to the tetrapod origin. This elaboration may have occurred by a simultaneous reduction of the distal ectodermal fold of fish fins. Modulation of 5' Hoxd gene transcription, through tetrapod-specific digit enhancers, has been suggested as a possible evolutionary mechanism involved in these morphological transformations. Here, we overexpress hoxd13a in zebrafish to investigate the impact of increasing 5' Hoxd expression during fin development. This overexpression causes increased proliferation, distal expansion of chondrogenic tissue and finfold reduction. In addition, we also show that the tetrapod-specific 5' Hoxd enhancer CsC promotes similar expression in zebrafish fins and mouse limbs. Our results support the idea that modulation of 5' Hoxd gene expression, by acquisition of novel enhancer elements, offered the substrate for the evolution of fins and the origin of tetrapod limbs. Freitas et al provide functional evidence supporting the hypothesis that modulation of 5' Hoxd transcription, through the addition of novel enhancer elements, was a key evolutionary mechanism for the distal elaboration of vertebrate appendages. This elaboration evolved into the distal limbs of tetrapods and allowed the colonization of land by vertebrates. © 2012 Elsevier Inc.