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There is a general sense that indeterminate colitis (IC) runs an aggressive clinical course, is medically refractory, and is associated with higher pouch failure rates following restorative proctocolectomy. The question has been raised whether IC can be assigned to a diagnosis of Crohn’s disease or ulcerative colitis through the characterization of immunogenetic similarities, or whether IC may represent a distinct subgroup within these heterogeneous disorders. In this article, the use of serologic markers, genetics, and immune responses to understand the pathogenesis of inflammatory bowel disease (IBD) and define clinically important subgroups of patients will be discussed. Then, how these scientific advances have been applied to the entity of IC will be reviewed. Importantly, a recent prospective study suggests that the absence of IBD-associated serologic markers defines the majority of IC as a separate entity within the spectrum of IBD. The development of serologic, genetic, and immune response markers will allow for rational description of clinically important subgroups, redefine natural history, and predict responses to therapy in IBD.