Lee Denson and colleagues report the identification of a Crohn's disease–specific gene signature that distinguishes Crohn's disease from another form of inflammatory bowel disease (IBD), ulcerative colitis (J. Clin. Invest. doi:10.1172/JCI75436, 8 July 2014). The study used 359 samples from the RISK cohort to compare the ileal biopsies of treatment-naive pediatric cases from 3 groups—Crohn's disease with ileal inflammation (iCD), colon-only Crohn's disease (cCD) and ulcerative colitis—with non-IBD controls. In total, 1,281 genes were differentially expressed in 2 independent iCD groups in comparison to controls, making up the core iCD gene signature. In addition, 82% of genes in the core signature were also differentially expressed in cCD versus control biopsies, in comparison to just 18% in the ulcerative colitis versus control comparison. The authors used measures of microbial abundance from the ilea of additional RISK case samples to show that shifts in the microbial community were similar in the ilea of both iCD and cCD cases, identifying the ileum as the likely primary tissue of induction for Crohn's disease. Finally, the authors identified gene coexpression signatures characterized by the upregulation of DUOX2 and downregulation of APOA1 that distinguished both forms of Crohn's disease from ulcerative colitis. A model including these two coexpression signatures and microbial composition data was more predictive of 6-month steroid-free remission than a model including only clinical parameters.