In plants, resistance to a pathogen is frequently correlated with a genetically defined interaction between a plant resistance gene and a corresponding pathogen avirulence gene. A simple model explains these gene-for-gene interactions: avirulence gene products generate signals (ligands), and resistance genes encode cognate receptors. The A. thaliana RPS2 gene confers resistance to the bacterial pathogen P. syringae carrying the avirulence gene avrRpt2. A map-based positional cloning strategy was used to identify RPS2. The identification of RPS2 was verified using a newly developed transient assay for RPS2 function and by genetic complementation in transgenic plants. RPS2 encodes a novel 105 kDa protein containing a leucine zipper, a nucleotide-binding site, and 14 imperfect leucine-rich repeats.