The Toll-interleukin-1 receptor (TIR) domain is found in innate immune molecules of insects, animals, and plants. There is a marked conservation of the signaling pathways used by TIR domain-containing immune receptors in animals. In plants, pathways involving TIR domain-containing proteins are not as well understood, but data are beginning to suggest important differences between the functions of plant and animal proteins. Plant Resistance proteins use their TIR domains for pathogen detection, and they may also function in the nucleus to direct the expression of genes involved in defense responses. This shows that plants have used their TIR domains to perform a multitude of duties and have expanded the functions of the TIR domain beyond those seen in animals.