A fine characterization of genes encoding domains similar to plant resistance (R) proteins, in C. pepo proteome was conducted. R-proteins can be categorized according to the presence and organization of protein domains, such as Toll/Interleukin-1 receptor (TIR), coiled coil (CC), the nucleotide-binding site (NBS), leucine-rich repeats (LRRs). A total of 64 R-proteins (also called NLR, NB-LRR, NBS-LRR, or NB-ARC-LRR proteins) were identified (Supplementary Table 4). The CNL (Coiled coil, Nucleotide-binding site, Leucine-rich repeats) class was divided into sub-classes based on sequence similarity with the canonical CNLs that contain an EDVID amino-acid motif, and the RPW8-like proteins (Andolfo et al., 2014b). Interestingly, an expansion of RPW8-NLR genes (11 out of 64) in C. pepo was discovered. Diversely, C. melo, C. sativus, and C. lanatus presented only three RPW8-NLRs for each species (Figure 1A). It is now well-known that RPW8-NLRs can function as helper NLRs for well-defined NLR–mediated resistance responses. Thus, they may enhance the C. pepo defense system to offset its reduced number of NRL receptors available (Sanseverino and Ercolano, 2012). In addition, C. pepo RPW8-NLRs showed a very high homology to ADR1 (activated disease resistance 1), R-gene that confer resistance again Erysiphe cichoracearumi, the causal agent of Powdery Mildew (PM) in A. thaliana (Micali et al., 2008). PM disease, caused by Podosphaera xanthii (syn. Sphaerotheca fuliginea) has an important economic impact on C. pepo varieties. ADR1-like proteins expansion, identified in C. pepo, could suggest an adaptive diversification induced by specie-specific pathogen pressure (Andolfo and Ercolano, 2015).