Type 1 diabetes mellitus is an autoimmune disease caused by the immune-mediated destruction of insulin-producing pancreatic beta cells occurring in genetically predisposed individuals, with consequent hyperglycemia and serious chronic complications. Studies in man and in experimental animal models have shown that both innate and adaptive immune responses participate to disease pathogenesis, possibly reflecting the multifactorial pathogenetic nature of this autoimmune disorder, with the likely involvement of environmental factors occurring at least in a subset of individuals. As a consequence, components of both innate and adaptive immune response should be considered as potential targets of therapeutic strategies for disease prevention and cure. Here we review the contribution of innate immune response to type 1 diabetes, with a particular emphasis to Toll-like receptors (TLR) and NK cells.