The disease spectrum and natural course of Crohn's disease and ulcerative colitis are highly variable. The majority of Crohn's disease patients will require surgery at a certain stage in their disease compared to only a fraction of the ulcerative colitis patients. Similarly, some patients are destined to experience an indolent disease course while others will require early intensive therapy. Ideally, these subtypes of patients should be identified as early as possible with the help of reliable prognostic factors in order to guide personalized therapeutic decisions. In this review, the authors focused on the most relevant reports on the use of different prognostic factors to predict disease course, postoperative recurrence and response to therapy in patients with inflammatory bowel disease. The last 15 years have seen a wealth of novel genetic and serological markers of disease severity. Nevertheless, none of these markers have proven to be superior to careful clinical phenotyping and endoscopic features early in the disease course. Future attempts should apply an integrated approach that unites clinical, serological and (epi)genetic information with environmental influences, with a clear focus on the microbiome to ultimately identify molecular-based and clinically relevant subgroups.