Inflammation plays a detrimental role in islet transplantation leading to poor clinical outcomes. One of the major contributors of islet loss is IBMIR leading to 50% decrease in transplanted islet mass immediately post-transplantation. The detrimental effect of IBMIR was initially noted in Xenogenic and Allogenic islet transplantation, and later we reported that IBMIR also causes significant islet loss in auto-islet transplantation. Our group has mainly focused on anti-inflammatory strategies to dampen the effect of IBMIR. Consequently, we introduced the clinical use of Interleukin-1 beta blocker (Anakinra) along with Tumor Necrosis Factor alpha inhibitor (Etanercept) in islet transplantation. This protocol has shown improved outcomes compared to just Etanercept alone. We also explored the use of Nuclear Factor Kappa B inhibitor (Withaferin A) to prevent the early damage caused by IBMIR and obtained excellent results in vitro. Here, we have summarized our clinical and research findings pertaining to factors that affect the functional islet mass post-transplantation.