Plants have intrinsic structural, chemical, and proteomic defense mechanisms against pests that can be developed as natural biopesticides as an environmentally friendly and safe alternative. This review investigates advances in biopesticides, focusing on protease inhibitors (PIs) that interfere with the digestion of proteins in insect guts, adversely affecting insect nutrition, growth, and metabolism. One type of PI trypsin inhibitor [TI] was assessed from seeds of 56 plants belonging to 8 families for insecticidal and fungicidal activity with up to 90% effectiveness. Lepidopterans were the main insects causing the most damage to important cultivated crops, and TIs from Momordica cochinchinensis showed up to 80% inhibitory activity. They were selected for further assessment for their potential as biopesticides for pest management. TIs from M. cochinchinensis have been well characterized, and their small sizes, high potency, and genetic simplicity make them ideal candidates for development and commercialization as natural biopesticides.