TIR (Toll, interleukin- receptor, resistance protein) domains feature in a subset of plant NLRs (nucleotide-binding – leucine-rich repeat receptors - TNLs) that respond to plant pathogen effectors and trigger effector-triggered immunity (ETI). Following the demonstration that the TIR domains from the human protein SARM1 have enzymatic activity - cleavage of NAD+ (nicotinamide dinucleotide), such activity was also demonstrated for a number of plant TIR domains (1). We have studied the molecular and structural bases of these enzyme reactions and the role of the corresponding enzymatic products in signalling. In particular, we have defined the chemical structures of two cyclic ADP ribose isomers produced by NAD+ hydrolysis, 2′cADPR and 3′cADPR, which are cyclized by O-glycosidic bond formation between the ribose moieties (2). While 2′cADPR appears to be associated with ETI signalling, 3′cADPR appears to be associated with suppression of plant immunity. Our work has provided new information about how TIR domains work, how they produce signalling molecules and how these products signal, but much future work is needed to fill the gaps.