An enormous amount of pathoetiologic information continues to accrue from animal models of inflammatory bowel disease and study of the gut microbiome that is providing expanded insight into the causes and mechanisms of inflammatory bowel diseases. This knowledge is being translated into new therapeutics that are being tested in Crohn's and ulcerative colitis patients with an aim to enhance treatment responses by moving away from immunosuppression and toward immunomodulation. In the last decade, the frontier of emerging IBD therapy has been dominated by biological agents that specifically target pro-inflammatory cytokines most notably tumor necrosis factor-alpha. However, it is clear that the gaps in therapy (primary and secondary nonresponse and the potential for drug side effects and intolerances) continue. To fill these gaps, various approaches are being employed to develop novel strategies, from inhibiting additional pro-inflammatory cytokines to focusing on blocking inflammatory cell trafficking, decreasing inflammatory cell mass, enhancing regulatory cell function and reinforcing epithelial barrier function. To these ends, aggressive and innovative research is being pursued to develop more robust treatment strategies and identify key molecular targets.