Plants respond to a physical injury or biological attack by producing, among other compounds, an arsenal of defense proteins, secondary metabolites and phytohormones, all necessary for plant survival. Defense proteins include the group of serine protease inhibitors (SPI), proteins that interact with the active site of their target enzymes. The activity of these protease inhibitors has been exploited to combat insect pests. SPI is an interesting alternative to produce plants with improved resistance characters through selection in the field or expressing their genes in sensitive plants by genetic engineering. The alternative that these natural products offer makes them valuable for the control of several crop pests.