As opposed to man-made chemicals or environmental pollutants that get into our food supply, toxins can be present due to their natural occurrence in food. Natural toxins found inherently in foods of plant and animal origins serve specific functions in the plant and animal or evolved as chemical defenses against predators, insects, or microorganisms. Natural toxins in foodstuffs have diverse chemical structures and are vastly different in nature and toxicity, including aquatic biotoxins, cyanogenic glycosides, furocoumarins, lectins, mycotoxins, solanines and chaconine, poisonous mushrooms, pyrrolizidine alkaloids, etc., which can be harmful when consumed in sufficient quantities. New nutritional trends are significantly increasing foodborne outbreaks that remain a worldwide problem. “Foodomics”—a discipline that studies the Food and Nutrition domains through the application and integration of advanced -omics technologies to improve consumer’s well-being, health, and knowledge—has the potential to comprehensively elucidate what is in food, how this composition differs across the food systems, and how diet composition as an ensemble of foods guides outcomes for nutrition, health, and sustainability. The evolving behaviors of consumers, current production techniques, food processing strategies, shifts in climate, and the escalation of microbial resistance introduce vulnerabilities throughout the food production and distribution chains. These vulnerable points underscore the critical need for implementing foodomics methodologies and advanced protocols as complementary, data-driven approaches aimed at safeguarding food safety across the entire production and distribution lines. By addressing these critical control points, foodomics can minimize contamination risks from natural toxins while fostering advancements in nutritional science and promoting sustainable dietary practices.