Innate immunity represents the first line of defense against invading pathogens and noxious stimuli. The Toll-like receptors (TLRs) are essential innate immune receptors that alert the immune system to the presence of invading microbes. Emerging evidence shows that TLR signaling is important in allograft rejection. In a murine model, the rejection of minor mismatched allografts cannot occur in the absence of MyD88, an important TLR signal adaptor protein, owing to a defect in dendritic cell maturation, which leads to diminished T-helper cell type 1 immune responses. A recent clinical study also suggests that recipients with a mutant TLR4 genotype manifest reduced lung allograft rejection. Thus, innate immune signaling via TLRs is important for alloimmunity.