Inflammatory bowel disease (IBD) could be curable by “immune rest” and correction of the genetic predisposition inherent in allogeneic hematopoietic stem cell transplantation. However, balancing risks against benefits remains challenging. The application of mesenchymal stem cells (MSCs) serving as a site-regulated “drugstore” is a recent concept, which suggests the possibility of an alternative treatment for many intractable diseases such as IBD. Depending on the required function of MSC, such as a cell provider, immune moderator, and/or trophic resource, MSC therapy should be optimized to maximize its therapeutic benefit. Therapeutic effects do not always require full engraftment of MSCs. Therefore, optimization of pleiotropic gut trophic factors produced by MSCs, which favoring not only regulating immune responses but also promoting tissue repair, must directly enhance new drug discoveries for treatment of IBD. Stem cell biology holds great promise for a new era of cell-based therapy, sparking considerable interest among scientists, clinicians, and patients. However, the translational arm of stem cell science remains in a relatively primitive state. Although several clinical studies using MSCs have been initiated, early results suggest several inherent problems. In each study, optimization of MSC therapy appears to be the most urgent problem, and can be resolved only by scientifically unveiling the mechanisms of therapeutic action. In the present review, the authors outline how such information would facilitate the critical steps in the paradigm shift from basic research on stem cell biology to clinical practice of regenerative medicine for conquering IBD in the near future.