Nonimmune cells have traditionally been viewed as target cells of the aberrant inflammatory process present in chronic immune-mediated conditions such as inflammatory bowel disease (IBD). However, the discovery that many of the functions traditionally attributed to immune cells are also performed by nonimmune cells has caused a shift to a multidirectional hypothesis in which nonimmune cells and acellular elements play active roles. Many types of interactions occur within this multidirectional system, and the difficulties associated with modeling these complex interactions currently limit our understanding of the cellular network that occurs in IBD. I describe the current knowledge of the roles played by nonimmune cells in the pathogenesis of IBD, as they emerge as crucial alternative targets for therapeutic intervention.