This chapter summarizes evidence that intestinal myofibroblasts, also called intestinal stromal cells, are derived in the adult from tissue mesenchymal stem cells under homeostasis and may be replenished by bone marrow mesenchymal stromal (stem) cells that are recruited after severe intestinal injury. A comparison of mechanism of immunosuppression or tolerance by adult intestinal stromal cells (myofibroblasts) is almost identical with those reported for mesenchymal stem cells of bone marrow origin. The list of suppression mechanisms includes PD-L1 and PD-L2/PD-1 immune checkpoint pathways, soluble mediator secretion, toll-like receptor-mediated tolerance, and augmentation of Treg cells. Further, both mesenchymal stem cells and intestinal stromal cells express an almost identical repertoire of CD molecules. Lastly, others have reported that isolate intestinal stromal cells are capable of differentiating into bone and less well into chondrocyte, but not into adipocytes, a finding that we have confirmed. These findings suggest that intestinal stromal cells (myofibroblasts) are partially differentiated adult, tissue-resident stem cells which are capable of exerting immune tolerance in the intestine. Their role in repair of inflammatory bowel disease and immune suppression in colorectal cancer needs further investigation.