Tumor necrosis factor α inhibitors dramatically changed the management of moderate-to-severe phenotypes of ulcerative colitis. The recent incoming of vedolizumab, which targets gut-specific leukocyte trafficking, provides a new biologic option for these patients. Areas covered: This review focuses on the rationale of use, efficacy, and safety profile of all biologics currently approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of ulcerative colitis, including tumor necrosis factor α inhibitors (Infliximab and biosimilars, adalimumab, and golimumab), and the more recent vedolizumab. Expert opinion: Although biologics have been available in clinical practice for ulcerative colitis for about 15 years, there are several aspects that have not been fully understood yet: we know that they work, but we still don't know which subsets of patients benefit more, and how to optimize their use. All these unresolved problems are at least partly due to the discrepancy observed between phase II/III clinical trials of all biologics currently used in ulcerative colitis and in clinical practice.