A comparative analysis among C. pepo, C. melo, C. sativus, C. lanatus, and A. thaliana were performed to obtain functional information on our proteome. A total of 18,742 orthologous groups (OGs), which included 107,386 sequences, were identified (Supplementary Table 5). 9,453 OGs enclosed 69,982 sequences and were highly conserved in all analyzed genomes (Figure 1B). A core Cucurbitaceae proteins (9,465 sequences) clustered in 2099 OGs were detected. About 65% (22,214) of C. pepo predicted proteins were grouped in 13,953 OGs (Figure 1B). Several C. pepo gene family expansions associated to transmembrane R-genes were discovered. One hundred zucchini proteins, annotated as Receptor-like Kinase (RLK) and Receptor-like Protein (RLP) were clustered in five OGs (OG_00004, OG_00027, OG_00038, OG_00053, OG_01889, and OG_00579) and associated a well-characterized R-genes (Supplementary Table 5). Probably the expansion of cell surface receptors (RLKs and RLPs) and relative strengthening of first defence line represent adaptive dynamics to balance the limited number of cytoplasmic receptors (NRLs) (Andolfo and Ercolano, 2015). The C. pepo gene family expansions could be associated to the cucurbit-common tetraploidization recently identified by Wang et al. (2017). Furthermore, we identified a number of gene families related to important agronomical traits. Fourteen OGs related to OVATE gene family grouped 19 zucchini genes. OVATE is an important locus for fruit shape determination and plant development (Rodríguez et al., 2011). We identified three zucchini ortholog genes to PSY1 and PSY3 melon genes that putatively involved in carotenoid metabolism and fruit ripening (Garcia-Mas et al., 2012). The Cup000085g037789 is the ortholog gene of OR, a cloned gene that governs the fruit flesh colur in melon and in other important crops (Tzuri et al., 2015). Comparative analysis of C. pepo proteome can be used to identify orthologous genes for functional study. Our dataset represented a very important resource to reduce the plant breeding work for the identification of candidates for important agronomical traits (Supplementary Table 5).