Vertebrate heart development is derived from paired primordia of anterior dorsolateral mesoderm expressing Nkx2.5 and GATA4 transcription factors. Yet growth factors and intracellular pathways specifying heart precursor gene expression are poorly understood. In the present work, we investigated the signaling events initiating Nkx2.5 expression in Xenopus laevis. We describe here that fibroblast growth factor (FGF) initiates the expression of Nkx2.5 without affecting GATA4. At gastrula, FGF3 is expressed in anterior neural ectoderm, and results presented here indicate that this tissue is involved in the induction of Nkx2.5 expression in neighboring lateral tissues. Further studies indicate that the intracellular p38 MAPK and the CREB transcription factor function downstream of FGF to initiate Nkx2.5 expression. Activation of the p38 MAPK pathway and of the CREB protein is both necessary and sufficient for the initial expression of Nkx2.5. Therefore, we would like to suggest that FGF expressed in anterior neural ectoderm is a major inducer of Nkx2.5 expression in neighboring cells. In these cells, FGF activates an intracellular p38 MAPK signaling pathway and its downstream target, the CREB transcription factor, all participating in the expression of Nkx2.5 in cardiac progenitors.