Toll-like receptors recognize a diverse range of molecules derived from pathogens as well as host cells. As the number and diversity of TLR ligands and host factors increase, more questions are being raised. Here, we review recent advances toward understanding the molecular and cellular mechanisms underlying TLR-mediated direct or indirect recognition of their diverse range of ligands, including lipids, proteins, and nucleic acids. The elucidation of such mechanisms may represent a key for developing novel immunotherapeutics for infectious diseases, allergies, or cancer and to intervene in immunological disorders such as autoimmune diseases.