Host immune responses to commensal flora and enteric pathogens are known to influence gene expression in the intestinal epithelium. Although the Cdx family of caudal-related transcription factors are critical regulators of gene expression in the intestinal epithelium, the effect of intestinal immune responses on Cdx expression and function have not been determined. We have shown that both bacterial colonization and Th2 immune stimulation by intestinal nematode infection induce the expression of the intestinal goblet cell-specific gene RELM. In this study, we investigated the transcriptional regulation of RELM and its isoforms RELM and RELM to ascertain the role of Cdx in modifying intestinal gene expression associated with both innate and adaptive immune responses. Analysis of the RELM promoter showed that Cdx2 plays a critical role in basal gene activation in vitro. This was confirmed in vivo using transgenic mice where ectopic gastric and hepatic expression of Cdx2 induces the expression of RELM, but not RELM or RELM, exclusively in the stomach. Although there was no quantitative change in colonic Cdx2 mRNA expression, protein distribution, or phosphorylation of Cdx2, bacterial colonization induced the expression of RELM, but not RELM or RELM. In contrast, parasitic nematode infections activated the colonic expression of all three RELM isoforms without any alteration in Cdx2 expression. These results demonstrated that Cdx2 participates in directing intestine-specific expression of the RELM isoform in the presence of commensal bacteria, and that adaptive Th2 immune responses to intestinal nematode infections can activate intestinal goblet cell-specific gene expression independent of Cdx2.