Type 1 diabetes mellitus (T1DM) is a chronic disorder of glucose metabolism due to autoimmune destruction of insulin producing β-cells. Although insulin therapy is the standard treatment for T1DM, islet transplantation, which has emerged as an alternative to insulin injection, offers a more physiologic means of glycemic control. Unfortunately, the sustainability of islet function is poor. Most islet recipients experience loss of graft function and need to resume insulin therapy. Post-transplant inflammation, allograft rejection and anti-rejection drug toxicity are several factors that contribute to the loss of graft function. The primary cause of islet graft impairment immediately after transplantation is inflammation. Our aim is to prevent or minimize islet dysfunction after transplantation. The growing tempo of discoveries in stem cell therapies has opened avenues to explore improvements in islet graft survival. Mesenchymal stem cells are currently being examined for clinical therapies of various inflammatory disorders, such as sepsis and graft versus host disease. The objective of the first study is to examine the cytoprotective effects of MSCs on islets in the presence of pro-inflammatory cytokines. Human islets were co-cultured with bone marrow derived MSCs followed by exposure to pro-inflammatory cytokines in vitro. Glucose stimulated insulin secretion was preserved and β-cell apoptosis was prevented in the islets cultured with MSCs. However, the mechanism of protection is unclear. In the second study, we speculated the protection conveyed by MSCs was dependent on the physical interaction between islets and MSCs. Direct contact in islet and MSC co-cultures showed favorable results. When islets and MSCs were separated by a barrier, the MSCs were able to preserve islet function, but insulin content was decreased. We concluded that direct contact with MSCs is more beneficial than indirect contact for human islets. In the third study, the protective effect of MSCs on islets was examined in a preclinical mouse model of islet transplantation. The kidney is not an optimal site to assess the beneficial effect of co-transplanting islets and MSCs. On the other hand, intravenous MSC injection after islet transplantation improved islet function, but the effect was short-lived. These results suggest that MSCs are a promising solution to prolong islet graft function.