The increase of pro-inflammatory cytokines and oxidative stress leads to beta-cell damage and promotes beta-cells apoptosis, in types I and II of diabetes mellitus. Therefore, blocking of pro-inflammatory cytokines should be an effective way for the treatment of diabetes mellitus. When IL-1 occupies its receptor, various pro-inflammatory events are initiated including the synthesis and releases of chemokines and these chemokines attract neutrophils, macrophages, and lymphocytes that cause tissue inflammation. IL-1Ra is a naturally occurring cytokine and is the inhibitor of IL-1. When IL-1Ra binds to the IL-1 receptor, binding of IL-1 is blocked by IL-1Ra and pro-inflammatory signal from IL-1 receptor is stopped. There are mounting evidences to suggest that anti-inflammatory IL-1Ra reduces the inflammatory effects of IL-1 and preserves cell function in both types of diabetes. Therefore, IL-1Ra maybe a new therapeutic agent for diabetes mellitus types I and II. Mesenchymal stem cells (MSCs) are self-renewable multipotent stromal cells that have immunomodulatory capacity. Recently, well characterized subpopulations of MSCs which express IL-1Ra have been described. IL-1Ra expressed by these MSCs effectively binds to IL-1 receptor and protects tissues from inflammation-induced injuries. It has been previously shown that bone marrow-derived MSC therapy could be considered for the treatment of diabetes mellitus type 1 and complications of diabetes mellitus. This review presents understanding of potential use of IL-1Ra and MSCs as modulators of diabetogenesis.