Islet transplantation is an extremely effective therapy for patients with type I diabetes, providing tight control of blood glucose and persistent insulin release. Islet grafts struggle with various stress responses and immunity attacks, which contribute to loss of islet grafts in the long term. In this review we focus upon the innate immunity and heat shock responses, which are closely relevant to the outcome of islet grafts. Potential strategies provided by more comprehensive interventions to control innate immunity and by selective induction of heat shock proteins may ameliorate the outcome of islet transplantation.