Classical genetic and molecular data show that genes determining disease resistance in plants are frequently clustered in the genome. Genes for resistance (R genes) to diverse pathogens cloned from several species encode proteins that have motifs in common. These motifs indicate that R genes are part of signal-transduction systems. Most of these R genes encode a leucine-rich repeat (LRR) region. Sequences encoding putative solvent-exposed residues in this region are hypervariable and have elevated ratios of nonsynonymous to synonymous substitutions; this suggests that they have evolved to detect variation in pathogen-derived ligands. Generation of new resistance specificities previously had been thought to involve frequent unequal crossing-over and gene conversions. However, comparisons between resistance haplotypes reveal that orthologs are more similar than paralogs implying a low rate of sequence homogenization from unequal crossing-over and gene conversion. We propose a new model adapted and expanded from one proposed for the evolution of vertebrate major histocompatibility complex and immunoglobulin gene families. Our model emphasizes divergent selection acting on arrays of solvent-exposed residues in the LRR resulting in evolution of individual R genes within a haplotype. Intergenic unequal crossing-over and gene conversions are important but are not the primary mechanisms generating variation.Plants, like animals, are continually challenged by a myriad of potential pathogens. There is increasing evidence that defense systems of plants are at least as complex as vertebrate defense systems. Unlike animals, however, plants do not have a circulatory system and therefore cannot rely on a specialized, proliferative immune system. Each plant cell has to be capable of defense, even though this defense is coordinated locally and systemically between cells. There are a variety of types of resistance genes and mechanisms, some induced and some constitutive (for review, see Godiard et al. 1994;Michelmore 1995;Hammond-Kosack and Jones 1997). Often, although not always, disease resistance in plants is determined by single, usually dominant, genes. The recent cloning of several such resistance genes (R genes) is providing insight into their function and evolution. The defense system of plants may be ancient and predate the evolution of the immune system; genes similar to plant R genes have been identified in mammals van der Biezen and Jones 1998).In this review we consider what is known about the genomic organization and evolution of disease resistance genes in plants. The picture that is emerging for the organization and evolution of plant R genes is similar to that of the vertebrate major histocompatibility complex (MHC), T-cell receptor (TCR), and immunoglobulin genes. Therefore, although the specific types of genes involved are different, the evolutionary forces shaping the plant and vertebrate defense systems may be similar. We propose a model for the evolution of plant R genes that is adapted and expanded from a m...