The freshwater cnidarian polyp Hydra provides a useful model for studying regeneration. Previous work from our laboratory showed that head regeneration requires activation of the MAPK-CREB pathway. To identify extra-cellular ligands that may activate this pathway, we investigated FGF ligands. We isolated a partial FGF cDNA, FGF1l, not clearly related to any bilaterian FGF family, which is ubiquitously expressed by the endodermal epithelial cells in intact animals, and up-regulated in head- and foot-regeneratings tips from 2 to 32 hours after amputation. The RNAi knock-down of FGF1l gave rise to a “multi-headed” homeostatic phenotype, suggesting that FGF1l is involved in the repression of apical differentiation along the body column. Thanks to a commercial anti-FGF antibody, we also identified a distinct uncharacterized FGF protein we named FGF2l, expressed in the ectodermal epithelial cells either cytoplasmic or membrane-restricted. This study provides novel hints on the morphogenetic role of the FGF pathway in Hydra.