To defend themselves against invading microbes, plants rely on either a pathogen-associated molecular pattern (PAMP)-triggered system or an effector-triggered system. The latter is mainly mediated by the class of intracellular nucleotide-binding leucine-rich repeat (NLR) receptors, which can be divided into two groups that differ in their N-terminal structural element. CC-NLRs are characterized by an N-terminal coiled-coil element and are thought to act by assembling into ion channels upon activation. In contrast, TIR-NLRs are characterized by an N-terminal Toll/interleukin-1 receptor domain and act as either NADases and/or synthetases of cNMP derivatives. For both groups, structural biology tools have provided important insights into the mechanisms of activation and activity of these cornerstone proteins of plant immunometabolism. Using cryo-electron microscopy, we aim to support other i-HEAD projects in their quest to unravel the mechanisms of plant immunometabolism and to better understand the molecular components that allow plants to differentiate between beneficial and detrimental microbial interactions.