The 5′Hox genes have crucial functions in limb development in mammals, but whether these roles are conserved in non-mammalian tetrapods and in limb regeneration is poorly understood. Now, Takashi Takeuchi and colleagues use CRISPR/Cas9 to study the role of Hox13 genes in the newt Pleurodeles waltl. They show that Hoxa13, Hoxc13 and Hoxd13, but not Hoxb13, are expressed both in developing limbs and in blastemas. Yet, the knockout of Hoxa13 most strongly impairs digit formation and the normal development of carpal elements, whereas no apparent phenotypes are observed in Hoxc13 and Hoxd13 knockouts. Newt Hoxd13 likely has potential functions for digit formation because ectopic Hoxd13 expression in Hoxa13 knockout newts partially rescues limb development. However, expression of Hoxd13 in limb buds is restricted spatiotemporally and is strongly dependent on Hoxa13a. Lastly, the authors show using amputation of the forelimbs that Hox13 genes, and particularly Hoxa13, are also required for digit formation during limb regeneration. Collectively, these findings demonstrate that the role of Hox13 genes in limb development and regeneration is conserved in newts, thus establishing this system as a new model for studying Hox functions.