While food shortage remains a big concern in many regions around the world, almost one-third of the total food production is discarded as food loss and waste (FLW). This is associated with about one-quarter of land, water, and fertilizer used for crop production, even though resources and environmental constraints are expected to limit food production around the world. FLW reduction represents a potential opportunity to enhance both food security and environmental sustainability and therefore has received considerable attention recently. By reviewing the recent progress and new developments in the literature, this paper highlights the importance of FLW prevention as a complementary solution to address the Grand Challenge of global food security and environmental sustainability. However, raising awareness only is not enough to realize the expected FLW reduction. We identify the knowledge gaps and opportunities for research by synthesizing the strategies of FLW reduction and the barriers, including (1) filling the data gaps, (2) quantifying the socioeconomic and environmental impacts of FLW reduction strategies, (3) understanding the scale effects, and (4) exploring the impacts of global transitions. It is urgent to take more aggressive yet scientifically based actions to reduce FLW, which require everyone’s involvement along the food supply chain, including policy makers, food producers and suppliers, and food consumers.