To study the roles of key transcription factor networks, growth factors, and signaling molecules in the endoderm, notochord, and floorplate, we developed an inducible Cre-expressing system for altering gene function in this tissue. We generated an allele of Foxa2 that directs a tamoxifen-regulated Cre in the Foxa2 expression domain (Foxa2mcm). Activity of Foxa2mcm recapitulates endogenous Foxa2 expression in endoderm, notochord, and floorplate. Efficiency of the system in a given tissue type was dose- and timing-dependent. By comparing efficiency and location of Cre activity after administration of tamoxifen by oral gavage vs. intraperitoneal injection, we found that oral gavage achieves more rapid, robust recombination with less embryonic toxicity. This system will be useful for controlling the activity of floxed alleles at multiple stages of mouse embryogenesis and fetal development. Developmental Dynamics 237:447–453, 2008. © 2007 Wiley-Liss, Inc.