Toll-like receptors (TLRs) play a crucial role in the recognition of invading pathogens and the activation of subsequent immune responses against them. Individual TLRs recognize distinct pathogen-associated molecular patterns (PAMPs). The TLR family harbors an extracellular leucine-rich repeat (LRR) domain as well as a cytoplasmic domain that is homologous to that of interleukin-1 receptor (IL-1R). Upon stimulation, TLR recruits IL-1R-associated protein kinases via adaptor MyD88, and finally induces activation of nuclear factor-κB and mitogen-activated protein kinases. However, the response to TLR ligands varies, indicating the diversity of TLR signaling pathways. Besides MyD88, several novel adaptor molecules have recently been identified. Differential utilization of these adaptor molecules may provide the specificity in the TLR signaling. Characterization of each TLR signaling pathway will reveal the molecular mechanism of self-tolerance as well as cross-tolerance in response to a variety of PAMPs.