The gastrointestinal tract uses a system of tolerance and controlled inflammation to limit the response to dietary or bacteria-derived antigens in the gut. When this complex system breaks down, either by a chemical or pathogenic insult in a genetically predisposed individual the resulting immune response may lead to inflammatory bowel disease. Although the aetiopathogenesis of inflammatory bowel disease remains unsolved current evidence indicates that defective T-cell apoptosis and impairment of intestinal epithelial barrier function play important roles. In inflammatory bowel disease, it has been reported that activation of macrophages seems to be as important as increased production of the macrophage-derived cytokines such as TNF-alpha, IL-1 and IL-6. The triggering factor for this cascade is still to be elucidated as to whether it represents an auto-antigen or a hetero-antigen. It has been also demonstrated that a serologic anti-microbial response exists. This response includes antibodies against saccharomyces cerevisiae (ASCA), E. coli outer membrane porin C (Omp-C), flagelin (cBir1) and pseudomonas aeroginosa (I2). Host response to microbial pathogens includes self-defense mechanisms including defensins, pattern recognition receptors and Toll-like receptors. Neuroimmunomodulation in inflammatory bowel disease (IBD) is another interesting approach with implications on the influence of brain-gut axis on intestinal inflammation and its perpetuation. It is probable that inflammatory bowel disease represents a heterogenic group of diseases that share similar mechanisms of tissue damage but have different initiating events and immunoregulatory abnormalities. A better understanding of all these events will hopefully provide new insights into the mechanisms of epithelial responses to microorganisms and ideas for therapies.