The discovery of the enzymatic activity of the toll/interleukin-1 receptor (TIR) domain protein SARM1 five years ago preceded a flood of discoveries regarding the nucleotide substrates and products of TIR domains in plants, animals, bacteria, and archaea. These discoveries into the activity of TIR domains coincide with major advances in understanding the structure and mechanisms of NOD-like receptors and the mutual dependence of pattern recognition receptor– and effector-triggered immunity (PTI and ETI, respectively) in plants. It is quickly becoming clear that TIR domains and TIR-produced nucleotides are ancestral signaling molecules that modulate immunity and that their activity is closely associated with Ca²⁺signaling. TIR domain research now bridges the separate disciplines of molecular plant- and animal-microbe interactions, neurology, and prokaryotic immunity. A cohesive framework for understanding the role of enzymatic TIR domains in diverse organisms will help unite the research of these disparate fields. Here, we review known products of TIR domains in plants, animals, bacteria, and archaea and use context gained from animal and prokaryotic TIR domain systems to present a model for TIR domains, nucleotides, and Ca²⁺at the intersection of PTI and ETI in plant immunity.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .