Toll-like receptors (TLRs) are type-I transmembrane proteins with extracellular leucine-rich repeat (LRR) motifs and an intracellular Toll/interleukin-1 receptor (TIR) domain. Members of the TLR family contribute both to cell-cell interactions and to signalling, linking extracellular signals to specific gene-expression programmes. Toll, the founding member of the TLR family, was initially implicated in the establishment of dorsoventral polarity in the early Drosophila melanogaster embryo 1 . Genetic analysis of Drosophila Toll and another Drosophila TLR, Toll2 (also called 18 wheeler (18w)), revealed an additional role in embryogenesis and post-embryonic development 2,3 . Functional studies in vertebrates have not uncovered a role for TLRs in development. Mammalian TLRs have essential roles in the direct recognition of infectious agents, initiating signalling through nuclear factor-kappa B (NF-κB), leading to the initiation of both innate and adaptive immune responses 4,5 . Similarly, Drosophila Toll also contributes to NF-κB-mediated host immune defences and is essential for resisting infections 6 ; although, in contrast to mammals, Drosophila Toll does not directly recognize microorganisms but is activated by its endogenous ligand, Spätzle. Such observations, and the recent accumulation of genomic and functional data in diverse organisms, are challenging the view that the insect and vertebrate innate immune systems share a common ancestry.Here, we review our knowledge of TLR distribution and function in the animal kingdom. After describing TLR structure in terms of domain organization, we report the distribution and diversification of TLR genes among the animal kingdom and outline their functions in model organisms. This survey confirms the ancient origin of TLR genes but reveals major differences in the way TLRs function among species. Finally, we discuss what this tells us about the ancestral TLR function, their evolution and the emergence of TLR-mediated immunity.Molecular signatures of TLRs TLR ectodomain. The main part of the TLR ectodomain is composed of LRR motifs. This ancient domain has been identified in many proteins in viruses, archaea, bacteria, plants, fungi and animals. It is defined by a 22 to 29 amino-acid repeat with characteristically spaced hydrophobic residues 7 . LRR motifs provide a versatile structural framework for the formation of protein-protein interactions 8 . However, TLR ectodomains also interact with lipids, carbohydrates and nucleic acids. The crystal structure of the extracellular region of human TLR3 reveals that the LRR motifs form a horseshoe-shaped solenoid that is directly involved in ligand interaction 9,10 (FIG. 1). This direct interaction has recently been reported for other TLR family members, including Drosophila Toll 11 , human and mouse TLR1, TLR2, TLR4, TLR5 , and murine TLR9 (ReFs 15,16