Food loss and waste (FLW) represents a major challenge for food systems sustainability and a growing concern in the political agenda of national governments and international organizations. This interest is primarily driven by the interrelated implications that FLW has with food security, human health, economic development, and ecosystems. The staggering amount of FLW currently generated along supply chains exacerbates global food system challenges, such as world population growth, change of dietary habits, energy intensity of agro-food systems, and food supply vulnerability due to climate change. In a life-cycle perspective, beyond representing a missed opportunity to feed the growing world population, FLW also puts a huge pressure on natural capital, in terms of natural resources consumption (e.g., fossil energy, water, fish stocks, agricultural land), environmental pollution (water, air, soil), GHG emissions, ecosystem resilience, and biodiversity loss. This chapter aims at analyzing food systems sustainability through the lens of the interrelated implications and impacts of FLW on production and consumption. First, it provides an overview of the debate around FLW definition and quantification. Then, it focuses on the causes and impacts of FLW and the related methodological challenges. Additionally, recent policy initiatives are discussed in a comparative perspective. Finally, challenges and future research needs are highlighted.