Resistance (R) proteins are involved in specific pathogen recognition and subsequent initiation of host defence. Most R proteins are nucleotide binding - leucine rich repeat (NB-LRR) proteins, which form a subgroup within the STAND (signal transduction ATPases with numerous domains) family. Activity of these multi-domain proteins depends on their ability to bind and hydrolyse nucleotides. Since R protein activation often triggers cell-death tight regulation of activation is essential. Autoinhibition, which seems to be accomplished by intramolecular interactions between the various domains, is important to retain R proteins inactive. This review summarizes recent data on intra- and intermolecular interactions that support a model in which pathogen perception triggers a series of conformational changes, allowing the newly exposed NB domain to interact with downstream signalling partners and activate defence signalling.