This chapter describes ten landmark studies that redefined gastroenterology across prevention, acute care, and chronic disease modification. In portal hypertension, early TIPS for high-risk variceal bleeding cut rebleeding and improved survival, while rifaximin (on lactulose) prevented recurrent hepatic encephalopathy and reduced hospitalizations. Alcoholic hepatitis (STOPAH) narrowed practice—pentoxifylline offers no benefit and prednisolone yields, at best, short-term gains with infection risk—underscoring alcohol cessation and supportive care. Chronic liver disease strategy pivoted from ineffective interferon maintenance (HALT-C) to targeted therapies: obeticholic acid improved biochemical control in PBC (with pruritus trade-offs), and long-term albumin (ANSWER) signaled fewer decompensations and better survival but faces real-world barriers. For metabolic liver disease, PIVENS established vitamin E (and signal for pioglitazone) as options for non-diabetic NASH without antifibrotic effect, reinforcing lifestyle change as first-line. In IBD, SONIC validated early infliximab–azathioprine combination for superior steroid-free remission and mucosal healing in Crohn’s, while OCTAVE introduced rapid, oral JAK inhibition for moderate–severe ulcerative colitis with distinct safety monitoring. In population health, COLONPREV showed FIT’s higher uptake can match one-time colonoscopy for cancer detection, though colonoscopy better captures advanced adenomas—highlighting that program effectiveness hinges on adherence, follow-up, and informed choice.