Abstract: As the demand for greener and more sustainable agriculture intensifies, botanical pesticides are attracting renewed global interest owing to their environmental compatibility, distinctive modes of action, and reduced risk of resistance development. Conventional discovery strategies have largely relied on a linear workflow of extraction, screening, isolation, and identification, leading to the commercialization of representative products such as azadirachtin and rotenone. Yet these strategies still face significant bottlenecks, including low efficiency, heavy resource consumption, and difficulty in discovering active compounds with novel mechanisms of action. These obstacles lead to lengthy development cycles and high R&D costs for botanical pesticides. In this Review, we highlight several emerging directions that are redefining plant-derived pesticide research. These include moving beyond conventional in vitro activity screening to identify endogenous plant defense-inducing compounds; leveraging plant-microbe interactions to mine symbiotic and antagonistic microorganisms for new chemical entities; integrating insect-plant coevolution to identify targets involved in insect-specific detoxification and adaptive responses; integrating genomics with metabolic pathway analysis to predict biosynthetic gene clusters associated with potentially active metabolites and coupling these approaches with virtual screening for more efficient bioactivity assessment; and reconstructing plant biosynthetic pathways in microbial chassis through synthetic biology to enable scalable and sustainable production of high-value bioactive compounds. Together, these emerging perspectives point to a conceptual shift in plant-derived pesticide discovery: from passive, resource-dependent screening towards proactive, technology-driven design. Embracing this shift is expected to substantially improve the efficiency and success rate of traditional screening, accelerate the development of next-generation biopesticides, and provide innovative solutions for safeguarding global food security and ecological health.