Toll-like receptors (TLR) are critical sentinels of the host innate immune system. Prior evidence has clearly demonstrated that these receptors are essential to immune recognition of invading pathogens. However, there is emerging evidence that TLR signaling participates in inflammation that is not driven by microorganisms. In the setting of solid organ transplantation, there is accumulating evidence, both in experimental and clinical studies, that TLR signaling is involved in the immune recognition of allografts. Further investigation of how innate immunity impacts solid organ transplantation will likely lead to improved therapeutics for transplant recipients.