Societal Impact StatementGossypol and its derivatives represent a class of toxic and immunosuppressive compounds that are naturally synthesized in cottonseed. These compounds pose several health hazards to humans and animals, such as heart and lung damage, breathing difficulties, and death in swine. In poultry, gossypol reduces egg production and slows growth. Studies have also shown that gossypol can indirectly harm humans and animals through the food chain. Although several physical and chemical approaches are adopted to reduce gossypol levels in cottonseed before food and feed processing, these techniques are expensive. Therefore, genetically regulating gossypol production in cotton could provide a cheaper alternative.SummaryCotton (Gossypium spp.), the most important fiber crop, is cultivated in over a hundred countries to provide raw materials for the growing textile industry. The seed obtained after delinting cotton is a rich source of protein with a vast potential for oil and feed production. Cottonseed oil production is estimated at 5.08 million metric tons and is expected to generate over 6.56 billion United States Dollars in revenue by 2029. The cake from defatted cottonseed is used as animal feed and food supplements. However, the contamination of gossypol in cottonseed limits its use. Gossypol ingestion impairs weight gain and causes anorexia, respiratory distress, and death under extreme exposure. This review highlights the significance of cottonseed oil and meal; the pharmacological uses and impact of gossypol; the chemistry, toxicity, and bioactivity of gossypol; and the physical and chemical methods used in gossypol removal during feed and food supplement processing. In addition, the biosynthetic pathway of gossypol and attempts to genetically transform some key regulators of this pathway to produce glandless cottonseed or reduce the gossypol levels in the seed are discussed.