The discovery of Toll-like receptor (TLR) in human opened up a fascinating chapter in the understanding innate-machineries for host pathogen interaction, which seems to be an ancient imprint of defense mechanism in plant, fly and human. At the same time the long sought after candidate gene at Lps locus and the missing partner for CD14 merged into the identification of TLR4. In recent years, genes for two microbial resistance loci in mice, BCG and Lps have been identified as Nramp-1 and TLR4 respectively, although a second candidate gene, Ran GTPase has also been reported for the Lps locus. Interestingly, all genes are defective in C3H/Hej mice due to single point mutations. Drosophila Malvolio represents Nramps, which are putative catatonic transporters and Drosophila Toll represents TLRs which have striking similarity with cytoplasmic domain of IL-1 receptor at   their C-terminus. Abnormal food habit of Drosophila  due to the defect in Malvolio may resemble Pica  symptoms in human due to the deficiency of iron, however, it is difficult to draw any analogy in respect  of intracellular pathogen resistance exerted by Nramp-1. The present knowledge on metal transporter- mediated host defense is just beginning to be elucidated, whereas Toll has already established its role in developmental and defense pathways of the fly. Additionally, a wealth of information regarding IL-1 receptor and Dorsal/NF-ĸB signaling pathways have facilitated a rapid progress and raised several possibilities for future TLR research. In this article, we attempted to summarize recent advances in this field and focus on the defense pathway shared with plant, fly and human.