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Transplantation of islets of Langerhans is an emerging treatment procedure for patients with severe type 1 diabetes, but despite recent progress the procedure is associated with massive tissue loss caused by an inflammatory reaction termed instant blood-mediated inflammatory reaction (IBMIR). This reaction involves activation of the complement and coagulation cascades, ultimately resulting in clot formation and infiltration of leukocytes into the islets, which leads to disruption of islet integrity and islet destruction.In this review we discuss basic mechanisms underlying the IBMIR and emerging strategies for therapeutic regulation of the IBMIR. These include the use of selective inhibitors of the coagulation and complement systems, different procedures to coat the surface of the islets as well as the development of composite islet-endothelial cell grafts.The IBMIR is a major cause of tissue loss in clinical islet transplantation, and most likely in other cell therapies in which cells are exposed to blood. Thus, it is an obvious target for therapeutic intervention. Due to its complexity, it is necessary to use different strategies to control the IBMIR.