A subset of patients with ulcerative colitis (UC) present with, or progress to, moderate to severe disease activity. These patients are at high risk for colectomy, hospitalization, corticosteroid dependence, and serious infections. The risk of life-threatening complications and emergency colectomy is particularly high among those patients hospitalized with acute severe ulcerative colitis. Optimal management of outpatients or inpatients with moderate to severe UC often requires the use of immunomodulator and/or biologic therapies, including thiopurines, methotrexate, cyclosporine, tacrolimus, TNF-α antagonists, vedolizumab, tofacitnib, or ustekinumab, either as monotherapy or in combination (with immunomodulators), to mitigate these risks. Decisions about optimal drug therapy in moderate to severe UC are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Therefore, the American Gastroenterological Association prioritized development of clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the Grading of Recommendations Assessment, Development and Evaluation framework. Focused questions in adult outpatients with moderate to severe UC included: (1) overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to TNF-α antagonists, (2) comparative efficacy and safety of biologic monotherapy vs combination therapy with immunomodulators, (3) comparative efficacy of top-down (upfront use of biologics and/or immunomodulator therapy) vs step-up therapy (acceleration to biologic and/or immunomodulator therapy only after failure of 5-aminosalicylates, and (4) role of continuing vs stopping 5-aminosalicylates in patients being treated with immunomodulator and/or biologic therapy for moderate to severe UC. Focused questions in adults hospitalized with acute severe ulcerative colitis included: (5) overall and comparative efficacy of pharmacologic interventions for inpatients refractory to corticosteroids, in reducing risk of colectomy, (6) optimal dosing regimens for intravenous corticosteroids and infliximab in these patients, and (7) role of adjunctive antibiotics in the absence of confirmed infections.