The clinical presentation at the time of diagnosis and the disease course of ulcerative colitis (UC) are heterogeneous and variable over time. In population-based epidemiological follow-up studies from the last decades, the extent of UC has shown only slight variation. At diagnosis, the initial extent is evenly distributed among proctitis, left-sided, and extensive colitis with some exceptions. The disease course may vary from a single attack to chronic symptoms that reduce the quality of life as well as lead to disease extension, colectomy or even to the development of colitis-associated colorectal cancer in some cases. Important predictive clinical factors and biomarkers of disease course have been under increasing scrutiny. Those identified may eventually lead to a more personalized, tailored therapy. In this review article, the authors summarize the available evidence on the natural history and predictive markers for evaluating the course of UC.