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 52Hoxd 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 52Hoxd 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 52Hoxd enhancer CsC promotes similar expression in zebrafish fins and mouse limbs. Our results support the idea that modulation of 52Hoxd gene expression, by acquisition of novel enhancer elements, offered the substrate for the evolution of fins and the origin of tetrapod limbs.