Experimental studies during the last decade have revealed a number of signaling pathways that are critical for the development and maintenance of the intestinal epithelium and that demonstrate the molecular basis for a variety of diseases. The Notch-Delta, Wnt, Hedge Hog, TGF-beta, and other signaling pathways have been shown to form and steadily maintain the crypt-villus system, generating the proper quantities of highly-specialized cells, and ultimately defining the architectural shape of the system. Based on the characterized phenotypes and functional defects of mice resulting from various targeted knockouts, and overexpression and misexpressions of genes, a picture is emerging of the sequence of gene expression events from within the epithelium, and in the underlying mesenchyme that contribute to the regulation of cell differentiation and proliferation. This review focuses on the contributions of multiple signaling pathways to intestinal epithelial proliferation, differentiation, and structural organization, as well as the possible opportunities for cross-talk between pathways. The Notch pathway's potential ability to maintain and regulate the intestinal epithelial stem cell is discussed, in addition to its role as the primary mediator of lineage specification. Recent research that has shed light on the function of Wnt signaling and epithelial-mesenchymal cross-talk during embryonic and postnatal development is examined, along with data on the interplay of heparan sulfate proteoglycans in the signaling process.