Plant pathogens rely on effectors that are delivered into host cells to cause diseases. To fight back, plants acquired nucleotide-binding site–leucine-rich repeat (NLR) resistance proteins to recognize these pathogen effectors directly or to detect the activities of these effectors indirectly, triggering effector-triggered immunity. In their new spotlight commentary titled "TIRggering cell death via two enzymatic reactions", Zhengquin Fu and his collaborators discuss recent discoveries on the biochemical functions of the TIR domains that NLR proteins carry in their N-terminal. A great perspective!