The phenomenon of protein promiscuity, in which multiple functions are associated with a single peptide structure, has gained attention in several research fields, including the plant defense field. With this in mind, this report intends to link various plant defense peptides with common scaffolds (defensins, cyclotides and 2S albumins), and multiple activities with the processes of promiscuity generation and protein evolvability. This link seems to create an efficient system of plant defense against insect pests and pathogens, and is thus essential to plant survival and evolution. This review also identifies future possibilities for the use of peptide promiscuity in designing novel drugs and synthetic biotechnological products.