Innate immunity represents the first line of defense against microbial invasion. Recent studies have determined that a group of germline-encoded receptors, termed Toll-like receptors (TLRs), are critical for recognizing foreign motifs on microbial organisms and initiating innate responses. An exciting area of research has recently linked activation of TLRs on antigen-presenting cells (APCs) to effective antigen presentation and activation of naive T cells. Most studies have shown that TLR-dependent immune function leads to T-helper 1 (TH1) immunity, although evidence also supports that TH2 immune responses may be initiated by TLR signaling in certain contexts. In either case, innate immune signaling via TLRs leads to a productive adaptive immune response. In contrast to studies in purely infectious models, emerging data from experimental and clinical studies have provided evidence that TLR immune function is important in acute allograft rejection. Specifically, MyD88, an important TLR signal adaptor, was found to be critical for the rejection of minor-mismatched skin allografts, and important for alloimmune priming and TH1 immunity against fully allogeneic skin grafts. Furthermore, a clinical study has shown that recipients with TLR 4 polymorphisms associated with endotoxin hyporesponsiveness manifest reduce acute lung allograft rejection. Collectively, these studies demonstrate that innate immunity is important for alloimmunity. Future therapeutic modalities that target innate rather than adaptive immune mechanisms represent a promising avenue for future studies in thoracic organ transplantation.