Gene inactivation of the orphan G protein‐coupled receptor LGR4, a paralogue of the epithelial‐stem‐cell marker LGR5, results in a 50% decrease in epithelial cell proliferation and an 80% reduction in terminal differentiation of Paneth cells in postnatal mouse intestinal crypts. When cultured ex vivo , LGR4‐deficient crypts or progenitors, but not LGR5‐deficient progenitors , die rapidly with marked downregulation of stem‐cell markers and Wnt target genes, including Lgr5 . Partial rescue of this phenotype is achieved by addition of LiCl to the culture medium, but not Wnt agonists. Our results identify LGR4 as a permissive factor in the Wnt pathway in the intestine and, as such, as a potential target for intestinal cancer therapy. There is a [Hot off the Press][1] (June 2011) associated with this Scientific Report. [1]: http://dx.doi.org/10.1038/embor.2011.97