Mesenchymal cells in the intestine comprise a variety of cell types, of diverse origins, functions, and molecular markers. They provide mechanical and structural support and have important functions during intestinal organogenesis, morphogenesis, and homeostasis. Recent studies of the human transcriptome have revealed their importance in development of colorectal cancer (CRC), and studies from animal models have provided evidence for their roles in pathogenesis of colitis-associated cancer and sporadic CRC.