Inflammatory bowel disease is triggered by, as yet, unknown factors in the background of a polygenic susceptibility. Recent technological advances have made it possible to unravel genetic etiology and transcriptomal signature patterns of such complex diseases. Combining murine models with patient-derived data has proven a powerful approach to understand early events of etiopathogenesis and has pointed towards a primary deficiency of the innate immunological barrier function in this group of diseases. One of the emerging elements from transcriptomal studies is the imbalance of cellular programs involved in antioxidants with a resulting preponderance of reactive oxygen species in the inflamed intestinal tissue. The understanding of the complex genetic and genomic risk map of disease genes will not only further our understanding of inflammatory bowel disease etiopathogenesis, but may ultimately lead to therapeutic strategies aiming at the restoration of impaired intestinal barrier function.