The intersection of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Endangered Species Act (ESA) presents one of the most complex regulatory challenges in U.S. agriculture. This paper explores the historical, legal, scientific, and practical dimensions of pesticide registration and endangered species protection. FIFRA requires EPA to balance pesticide benefits against risks to human health and the environment, while ESA mandates absolute protection of listed species without risk-benefit considerations. These differing statutory objectives have led to decades of procedural inefficiencies, litigation, and regulatory uncertainty. The paper reviews the evolution of consultation processes, including the ESA Workplan, Vulnerable Species Pilot Program, and Herbicide Strategy, and evaluates their scientific and economic implications. Key obstacles include resource limitations, litigation-driven timelines, and lack of harmonization between FIFRA’s national risk assessments and ESA’s species-specific evaluations. Recommendations emphasize integrating higher-tier science, improving species mapping, leveraging conservation programs, and fostering stakeholder collaboration to develop practical, science-based mitigation strategies that protect endangered species while sustaining agricultural productivity.