The pathogenesis of inflammatory bowel disease (IBD) is very complex, including a variety of genetic and environmental contributing factors. In this context, over the past few years, a picture of IBD as a primary defect of the innate immune system rather than the adaptive immune system has evolved. The intestinal antimicrobial barrier morphologically consists of a single layer of epithelial cells and the mucus and constitutes the first defense mechanism against the microbial burden of the gut. From a more mechanistic point of view, this barrier additionally depends on a crucial interplay between the mucus and antimicrobial peptides like for instance defensins. Disturbances in this system are in the pathophysiological center stage of IBD genesis and progression. In this article we will give a short overview about some of the key mechanisms in this context with special attention on defensins and the mucus layer.