Patients with ulcerative colitis (UC) can experience periods of recurrent disease activity with a range of symptoms, including abdominal pain, rectal bleeding, urgency, and diarrhea. Although long-term remission will be achieved and maintained in most cases, the course of UC varies from patient to patient. Patients can be defined according to whether they are in remission or have mild, moderate, severe, or fulminant disease, and hospitalization can occur under different circumstances. In these cases, determining the next course of therapy is essential. The aim of this article is to present an approach to the treatment of high-risk UC in both the outpatient and inpatient settings. Also presented is a critical appraisal of alternative and emerging approaches to the management of patients with high-risk UC. Fundamental principles are key in the management of high-risk UC, including discussing the goals of treatment with the patient and family, assessing each patient's risk level and prognostic factors in addition to disease activity to inform therapeutic choices, understanding drug mechanisms and pharmacokinetics, and using objective measures to monitor disease response. In the treatment of all patients with high-risk UC, a balanced approach to deciding between medical and surgical options must be maintained.