The importance of the widely spread leucine-rich repeat (LRR) motif was studied considering TLRs, the LRR-containing protein involved in animal immune response. The protein connects intracellular signalling with a chain of molecular interactions through the presence of LRRs in the ectodomain and TIR in the endodomain. Domain analyses with human TLR1-9 reported ectodomain with tandem repeats, transmembrane domain and TIR domain. The repeat number varied across members of TLR and remained characteristic to a particular member. Analysis of gene structure revealed absence of codon interruption with TLR3 and TLR4 as exceptions. Extensive study with TLR4 from metazoans confirmed the presence of 23 LRRs in tandem. Distinct clade formation using coding and amino acid sequence of individual repeats illustrated independent evolution. Although ectodomain and endodomain exhibited differential selection pressure, within the ectodomain, however, the individual repeats displayed positive, negative and neutral selection pressure depending on their structural and functional significance. © 2019, Indian Academy of Sciences.