While it is widely accepted that chronic diseases such as inflammatory bowel disease (IBD) may trigger negative psychological emotions such as distress and even depression, it is unknown if this response to a chronic illness like IBD is solely a psychological response to an adverse situation or whether it also represents a biological response, that is, the active inflammatory state of IBD intersecting with the pathobiology of what mediates mood and anxiety disorders. There is a bi-directionality between psychological comorbidity and IBD with each influencing the course of the other when they coexist. Furthermore, there is much to learn in terms of the underlying pathobiology of depression and anxiety and how this may impact on the pathobiology of IBD. Several important questions in regards to psychological comorbidity and IBD will be reviewed in this chapter.