The etiology of inflammatory bowel disease (IBD) is not fully understood but is likely influenced by numerous factors such as genetic predisposition, environmental factors, like the microbiota, and social behaviors, including smoking and diet. In addition to anti-tumor necrosis factor therapy, we now have integrin inhibitors that target lymphocyte trafficking to the gastrointestinal tract (vedolizumab and natalizumab); however, unmet medical needs remain. Although several immunologic pathways have been implicated in the pathogenesis of IBD, targeting these with drug therapy has produced mixed results. Recent drug failures, particularly anti-interleukin-17 (anti-IL17) in Crohn’s disease and anti-IL13 in ulcerative colitis, highlight our fundamental lack of understanding of the impact of pathogenic heterogeneity in the treatment of IBD. In addition to a “failure of mechanism,” other reasons for drug failure may include issues with the drug itself—for example, insufficient activity, or lack of targeting, inadequate trial design or dosing, or potentially our inability to characterize patients who may be more (or less) responsive to a specific therapy. This review summarizes some of the successes and failures and evaluates therapies currently under investigation for IBD.