Innate immunity is the first line of defense in guarding the host against foreign pathogenic invaders. Cells of the innate immune system express pattern recognition receptors, such as toll-like receptors (TLRs), that recognize common molecular patterns of bacteria and viruses. However, along with the recognition of foreign pathogens, TLRs have also been shown to respond to endogenous substrates including; RNA released from dead or dying cells, oxidized molecules such as low density lipoproteins, and free fatty acids. When TLRs are triggered, signal transduction occurs resulting in increased expression and production of various cytokines and costimulatory molecules. TLR activation due to the recognition of self endogenous antigen has been implicated in perpetuating multiple autoimmune responses by skewing immune responses toward strong proinflammation. TLR activation can prime an adaptive immune response, potentially possessing the ability to signal the generation of autoantibodies and autoreactive lymphocytes. Therefore, TLRs, their associated signaling molecules, and their triggered cytokines, are prime candidates for future research in type 1 diabetes (T1D) and autoimmunity. Recently, inflammation has been shown to be a component of type 2 diabetes (T2D). In T2D, signaling through TLRs, in association with free fatty acids, is correlated with insulin resistance. Furthermore, TLRs and their associated signaling molecules are increased in the adipose tissue of T2D patients where inflammatory cells can accumulate. This review focuses on innate immunity and TLR involvement in both T1D and T2D. Therapeutic measures to manipulate TLR signaling, the expression of signaling components, and inflammatory cytokines may help to alleviate the disease process.