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 (ASUC). Optimal management of outpatients or inpatients with moderate-severe UC often requires the use of immunomodulator and/or biologic therapies including thiopurines, methotrexate, cyclosporine, tacrolimus, tumor necrosis factor (TNF)-α antagonists, vedolizumab, tofacitnib or ustekinumab, either as monotherapy, or in combination (with immunomodulators), to mitigate these risks.