A non-specific immune response mediated predominantly by innate inflammatory processes related to mechanics and site, and pre-existing and transplant-induced auto- and allo-specific cellular immune responses (possibly promoted by the initial inflammation) play a major role in the loss of islets and islet function transplanted in the liver.  Although significantly improved by the implementation of the immunosuppression, our capacity of achieving long-lasting insulin independence in patients with T1D undergoing portal vein islet transplantation remains limited. This indicates that the detrimental impact of innate and adaptive immune responses is not fully contained by the current regimen of generalized immunosuppression. Prolong  intrahepatic islet survival, by increasing the potency of such regimen is not practicable, due to the likelihood of enhancing susceptibility to cancer and infections, and the toxicity that some of these drugs may have towards kidney functions and transplanted islets. Rather, it is intuitive that alternative strategies aimed at selectively inhibiting undesired islet-specific or non specific immune responses represent an ideal step towards a better management (i.e., weaning/withdrawal of generalized immune suppression) and outcome (i.e., long-lasting insulin independence) of islet transplanted T1D patients. Thrombo-embolic and necroinflammatory events occurring in the liver early after portal vein islet transplantation are thought to reduce the total islet mass by up to 75%. The magnitude of such loss represents a major factor necessitating the extremely large number of islets needed to achieve normoglycemia. A better understanding and control of these events - including their likely support to effector immune responses - is required if we are to develop ways to prevent them, improve intrahepatic islet engraftment, and achieve long-term tolerance.