Ulcer disease is an infectious disease, but for how much longer? Reports of a large number of non-infectious ulcers are becoming more frequent, paralleling the changing prevalence of Helicobacter pylori (H. pylori) in many parts of the world. This chapter will address factors involved in the increasing proportion of H. pylori-negative ulcers, the probable cause of such ulcers and the clinical implications related to their management. This discussion is currently most relevant to those regions of the world where the prevalence of H. pylori is already low or rapidly decreasing. However, it is possible that, even in other areas of the world, the prevalence of infection will also eventually change and H. pylori-negative ulcer disease will become more important.