Inflammatory bowel diseases (IBDs) are chronic in-flammatory disorders of the bowel, including ulcerative colitis and Crohn’s disease. A single etiology has not been identified, but rather the pathogenesis of IBD is very complex and involves several major and minor contributors, employing different inflammatory pathways which have different roles in different patients. Although new and powerful medical treatments are available, many are biological drugs or immunosuppressants, which are associated with significant side effects and elevated costs. As a result, the need for predicting disease course and response to therapy is essential. Major attempts have been made at identifying clinical characteristics, concurrent medical therapy, and serological and genetic markers as predictors of response to biological agents. Only few reports exist on how mucosal/tissue markers are able to predict clinical behavior of the disease or its response to therapy. The aim of this paper therefore is to review the little information available regarding tissue markers as predictors of response to therapy, and reevaluate the role of tissue factors associated with disease severity, which can eventually be ranked as tissue factor predictors. Five main categories are assessed, including mucosal cytokines and chemokines, adhesion molecules and markers of activation, immune and non-immune cells, and other mucosal components. Improvement in the design and specificity of clinical studies are mandatory to be able to classify tissue markers as predictors of disease course and response to specific therapy, obtain the goal of achieving personalized pathogenesisoriented therapy in IBD.