Toll-like receptor (TLR) signaling has been implicated in the inflammatory responses in intestinal epithelial cells (IECs). Such inflammatory signals mediate complex interactions between commensal bacteria and TLRs and are required for IEC proliferation, immune response, repair, and homeostasis. The upregulation of certain TLRs in colorectal cancer (CRC) tissues suggests that TLRs may play an essential role in the prognosis of chronic and inflammatory diseases that ultimately culminate in CRC. Here, we provide a comprehensive review of the literature on the involvement of the TLR pathway in the initiation, progression, and metastasis of CRC, as well as inherited genetic variation and epigenetic regulation. The differential expression of TLRs in epithelial cells has also been discussed. In particular, we emphasize the physiological role of TLR4 in CRC development and pathogenesis, and propose novel and promising approaches for CRC therapeutics with the aid of TLR ligands.