This review focuses on the dual role of IL-18 and the crucial function of its unique partner, IL-18BP, in regulating this cytokine to keep it in the normal range, and the strategies pursued by over ten pharmaceutical companies and startups to target IL-18 and IL-18BP in autoimmune diseases, rare mutations, cytokine storm, cancer, and COVID-19. The gene discussed is IL18BP; the disease is autoimmune disease.