The exact pathophysiology of inflammatory bowel disease (IBD) is still unknown. However, over the years important insights allowed the development of novel therapeutic approaches that are at the threshold of introduction into clinical practice, or at least in clinical trials. After being first described by Burrill B. Crohn, Crohn's disease, one of the two major forms of IBD, was perceived as an infectious disease. When the concept of autoimmune diseases was formulated, Crohn's disease and ulcerative colitis were thought to be members of this disease group. T cells certainly contribute to the chronification of the intestinal inflammation and targeting T cell migration has been introduced some years ago as a successful therapeutic approach in IBD. Despite the development of successful therapy based on this pathophysiological concept, IBD is no longer seen as a typical autoimmune disease. After the millennium, genome wide association studies on genetic variants and risk factors in these polygenetic diseases have told us a lot about pathogenetic pathways. However, genetic susceptibility explains only up to one third of the cases. Environmental factors also must play a role. Those environmental factors may "transfer" their disease-promoting potential into pathophysiological pathways with the intestinal microbiota as mediator. Hence, the intestinal microbiota has gained much attention as an important factor in disease development. Microbial factors, as well as other direct environmental influences, have been shown to affect epigenetic signatures, intestinal epithelial cells and the innate immune system, providing another important concept on how these diseases originate and can cause repeated flares at the same gut segments even after years of remission and after intermediate complete mucosal healing. Current pathophysiological concepts of IBD not only help us to better understand these diseases and develop new therapies. They also illustrate the evolution of basic scientific concepts over time and that sometimes partially or even largely abandoned concepts persistently influence out current thinking/clinical practice.