Toll-like receptors (TLRs) play a crucial role in the host defense against invading microorganisms by recognizing pathogen-associated molecular patterns (PAMPs). The anti-cancer effects of a number of microbial components, that have been used as adjuvants for the immunotherapy of cancers, are mediated through TLR signaling. However, cancer immunotherapy is not always successful because of the immunosuppression associated with cancer progression. Recently, a number of endogenous molecules have been reported to be ligands of TLRs. It has been suggested that the release of these putative endogenous ligands of TLRs during cancer progression may cause chronic inflammation leading to the recruitment of myeloid suppressor cells and down-regulation of T-cell and natural killer (NK) cell receptor zeta (ζ) chain resulting in T and NK cell dysfunction. However, the reported putative endogenous TLR ligands may have been contaminated with PAMPs. Further studies are necessary to define the existence of endogenous TLR ligands and their potential contribution to the immunosuppression in cancer.