TLR4 is a transmembrane receptor of the innate immune system that recognize LPS of gram-negative bacteria. Its stimulation induces pro-inflammatory responses and also modulates adaptive immunity. In this article, we discuss the role of TLR4 in the activation and proliferation of T cells at the onset of autoimmune diabetes. We review the pathways involved in these observations. Finally, we show how targeting TLR4, by a variety of strategies, can prevent the occurrence of the disease but also its recurrence after allogeneic islet of Langerhans transplantation.