Foxa2 is a forkhead transcription factor expressed in the node, notochord, floorplate, and definitive endoderm and is required in the foregut endoderm for the normal development of the endoderm‐derived organs, such as the liver, lung and pancreas. To conditionally inactivate genes in these tissues and organs, we have targeted a Cre recombinase into Exon 1 of the Foxa2 gene. We show, upon crossing to the ROSA26 reporter mice, that Cre expression from the Foxa2^iCre knock‐in allele specifically activates β‐galactosidase expression in the node, notochord, floorplate, and endoderm. In addition, we detect Cre recombination activity in the endoderm‐derived organs including lung, liver, pancreas, and gastrointestinal tract throughout development. These results demonstrate that the Foxa2^iCre knock‐in mice are a valuable tool to analyze gene function in endoderm progenitors and endoderm‐derived organs. Moreover, the widespread β‐galactosidase reporter activity in the endoderm suggests that Foxa2 marks a progenitor cell population, which gives rise to the majority of cells in endoderm‐derived organs. genesis 46:515–522, 2008. © 2008 Wiley‐Liss, Inc.