There is a consensus among epidemiologists that the worldwide incidence rate of type 1 diabetes has been rising in recent decades. The cause of this rise is unknown, but epidemiological studies suggest the involvement of environmental factors, and viral infections in particular. Data demonstrating a cause-and-effect relationship between microbial infections and type 1 diabetes and how viruses may cause disease in humans are currently lacking. However, new evidence from animal models supports the hypothesis that viruses induce disease via mechanisms linked with innate immune upregulation. In the BioBreeding Diabetes Resistant rat, infection with a parvovirus induces islet destruction via upregulation of the toll-like receptor 9 (TLR9) signaling pathway. Data from mouse models of diabetes implicate TLR2, TLR3, and TLR7 in the disease process. Understanding the link between environmental agents and innate immune pathways involved in early stages of diabetes may advance the design of immune interventions to prevent disease in genetically susceptible individuals.