Podosphaera xanthii is the main causal agent of powdery mildew (PM) on Cucurbitaceae. In Cucumis melo, the Pm-w resistance gene, which confers resistance to P. xanthii, is located on chromosome 5 in a cluster of nucleotide-binding leucine-rich repeat receptors (NLRs). We used positional cloning and transgenesis, to isolate the Pm-wWMR 29 gene encoding a coiled-coil NLR (CC-NLR). Pm-wWMR 29 conferred high level of resistance to race 1 of PM and intermediate level of resistance to race 3 of PM. Pm-wWMR 29 turned out to be a homolog of the Aphis gossypii resistance gene Vat-1PI 161375. We confirmed that Pm-wWMR 29 did not confer resistance to aphids, while Vat-1PI 161375 did not confer resistance to PM. We showed that both homologs were included in a highly diversified cluster of NLRs, the Vat cluster. Specific Vat-1PI 161375 and Pm-wWMR 29 markers were present in 10 - 13% of 678 accessions representative of wild and cultivated melon types worldwide. Phylogenic reconstruction of 34 protein homologs of Vat-1PI 161375 and Pm-wWMR 29 identified in 24 melon accessions revealed an ancestor with four R65aa -a specific motif in the LRR domain, evolved towards aphid and virus resistance, while an ancestor with five R65aa evolved towards PM resistance. The complexity of the cluster comprising the Vat/Pm-w genes and its diversity in melon suggest that Vat-homologs may contribute to the recognition of a broad range of yet to be identified pests and pathogens.