Fibroblast growth factor (FGF) activates a protein kinase cascade in SK‐N‐MC cells that regulates gene expression at a cyclic‐AMP response element (CRE) by stimulating the transcriptional activity of CREB. The activation of CREB is prevented by a dominant negative mutant of Ras and triggered via the same site (Ser133) that becomes phosphorylated in response to cyclic AMP and Ca2+. However, the effect of FGF is not mediated by cyclic AMP‐dependent protein kinase, TPA‐sensitive isoforms of protein kinase‐C, p70S6K or p90rsk (all of which phosphorylate CREB at Ser133 in vitro). Instead, we identify the FGF‐stimulated CREB kinase as MAP kinase‐activated protein (MAPKAP) kinase‐2, an enzyme that lies immediately downstream of p38 MAP kinase, in a pathway that is also stimulated by cellular stresses. We show that MAPKAP kinase‐2 phosphorylates CREB at Ser133 in vitro, that the FGF‐ or stress‐induced activation of MAPKAP kinase‐2 and phosphorylation of CREB and ATF‐1 are prevented by similar concentrations of the specific p38 MAP kinase inhibitor SB 203580, and that MAPKAP kinase‐2 is the only detectable SB 203580‐sensitive CREB kinase in SK‐N‐MC cell extracts. We also show that transfection of RK/p38 MAP kinase in SK‐N‐MC cells, but not transfection of p44 MAP kinase, activates Gal4‐CREB‐dependent transcription via Ser133. These findings identify a new growth factor and stress‐activated signaling pathway that regulates gene expression at the CRE.