The inflammatory bowel diseases ulcerative colitis and Crohn's disease (CD) are heterogeneous syndromes representing the outcome of the colliding influences of shared and distinct genetic risk factors, environmental or lifestyle modifiers and immune effector mechanisms. Identification of specific genetic risk factors has provided a glimpse of potential pathways of tissue damage. Defective mucosal clearance of bacteria (commensals and pathogens), including phagocytic cell dysfunction, appears to be common in CD, but distinct inputs to a final common pathway of tissue damage may account for heterogeneity. Regardless of the genetic risk, the primacy of environmental or lifestyle risk factors is evident and can be linked to changes in the gut microbiota, particularly in early life. Improved understanding of the molecular basis of host–microbe interactions in the gut promises novel therapeutic strategies. Thus, the emerging drug therapy for patients with these diseases is moving from trials of empiric possibilities to rational drug design with exciting prospects already at hand.