Randomized controlled trials with direct comparisons between the different available biological agents in ulcerative colitis are lacking. The comparative efficacy, safety and tolerability, patient profile, patient preference and costs should be taken into account when choosing an appropriate first-line biological. Tumor necrosis factor antagonists have a systemic mode of action, while vedolizumab is mainly gut-selective, and this influences the clinical profile of both treatment options. Tofacitinib will further expand the therapeutic armamentarium in ulcerative colitis. Results of ongoing head-to-head trials between biological agents are likely to change clinical practice in the near future. Biomarkers that predict response to different treatment options in an individual patient are warranted.