Mesenchymal-epithelial crosstalk plays a crucial role in organ development and stem cell function. However, the identity of the mesenchymal cells involved in this exchange was unclear. Recent significant advances in single-cell transcriptomics have defined the heterogeneity of these mesenchymal niches. By combining multiomic profiling, animal models, and organoid culture, new studies have not only demonstrated the roles of diverse mesenchymal cell populations but also defined the mechanisms underlying their regulation of niche signals. Focusing on several digestive organs, we describe how similar and diverse mesenchymal cell populations promote organ development and maintain proper stem cell activity, and how the heterogeneity of mesenchymal niches is altered in digestive diseases such as inflammation and cancer.