The plant immune system relies on nucleotide-binding domain leucine-rich repeat (NLR) immune receptors to detect the presence or activity of pathogen virulence proteins that function in the host cytoplasm. These receptors often underlie disease resistance traits important for crop protection. One major class of NLRs employ an N-terminal Toll/Interleukin-1 Receptor (TIR) domain to signal downstream for cell death and resistance. TIR domains were recently discovered to be NADases that process NAD+, and related molecules, into a variety of novel small molecule signals. Plant TIR domains appear to have both a spectrum of products and a wide range of cell death-triggering activity. To better understand how TIR domains function we have exploited the diversity of structure and function of ~150 TIR domains in Arabidopsis to inform the design of synthetic TIRs. Using these synthetic TIRs, we test structure/function hypotheses proposed by the natural variation present in the Arabidopsis TIRome. By better understanding the structural requirements for TIR domain function, we hope to enable rational engineering of plant immunity to limit the costs of defense while maintaining disease resistance.