Abstract Background In plant genomes, NB-LRR based resistance (R) genes tend to occur in clusters of variable size in a relatively small number of genomic regions. R-gene sequences mostly differentiate by accumulating point mutations and gene conversion events. Potato and tomato chromosome 4 harbours a syntenic R-gene locus (known as the R2 locus in potato) that has mainly been examined in central American/Mexican wild potato species on the basis of its contribution to resistance to late blight, caused by the oomycete pathogen Phytophthora infestans . Evidence to date indicates the occurrence of a fast evolutionary mode characterized by gene conversion events at the locus in these genotypes. Results A physical map of the R2 locus was developed for three Solanum tuberosum genotypes and used to identify the tomato syntenic sequence. Functional annotation of the locus revealed the presence of numerous resistance gene homologs ( RGHs ) belonging to the R2 gene family ( R2GH s) organized into a total of 4 discrete physical clusters, three of which were conserved across S. tuberosum and tomato. Phylogenetic analysis showed clear orthology/paralogy relationships between S. tuberosum R2GH s but not in R2GH s cloned from Solanum wild species. This study confirmed that, in contrast to the wild species R2GH s, which have evolved through extensive sequence exchanges between paralogs, gene conversion was not a major force for differentiation in S. tuberosum R2GH s, and orthology/paralogy relationships have been maintained via a slow accumulation of point mutations in these genotypes. Conclusions S. tuberosum and Solanum lycopersicum R2GH s evolved mostly through duplication and deletion events, followed by gradual accumulation of mutations. Conversely, widespread gene conversion is the major evolutionary force that has shaped the locus in Mexican wild potato species. We conclude that different selective forces shaped the evolution of the R2 locus in these lineages and that co-evolution with a pathogen steered selection on different evolutionary paths.