The global food system faces numerous challenges, with food loss, waste, and safety emerging as key concerns. This chapter provides a comprehensive analysis of these critical issues, starting with an examination of global food loss and waste statistics. The main causes of food loss resulting from inefficiencies in production, handling, and distribution, are thoroughly explored. In contrast, food waste—which occurs at the retail and consumer levels due to improper storage, over-purchasing, and mismanagement—is also analyzed, highlighting the key differences between the two. Food spoilage is addressed as a major contributor to food waste, with a focus on its etiology and the factors that influence it. Various methods for detecting food spoilage are discussed, including microbiological identification techniques, biosensors, and chemical methods. Prevention strategies, particularly the application of hurdle technology, are also highlighted for their role in enhancing food preservation. The chapter concludes by addressing food safety as a global challenge. It offers a historical perspective on food safety and examines modern food control systems, such as the Hazard Analysis and Critical Control Points (HACCP) system. A holistic One Health approach, formerly known as One Medicine, to food safety strategies is proposed, addressing both chemical and microbial contaminants, as well as the growing issue of antimicrobial resistance, which threatens the safety and sustainability of the global food supply.