Ulcerative colitis has baffled researchers since the early 20(th) century. The prevailing explanation attributes the chronic recurring episodes of bloody diarrhea and abdominal pain to some form of immune abnormality, despite the lack of supporting evidence. This highlights the critical need for innovative research directions and methodologies to uncover the cause and develop a cure for this disease. By analyzing existing data from less than a dozen previously published studies, a novel, evidence-based pathogenesis was constructed, implicating colonic epithelial hydrogen peroxide as a causal factor in the development of this disease. This newly identified mechanism informed the creation of a groundbreaking class of therapeutics, known as reducing agents, which have demonstrated remarkable success in resolving colonic inflammation and restoring colonic health in patients with refractory ulcerative colitis. This paper outlines the timeline of these publications and reinterprets the findings within the context of contemporary biomedical science.