Inflammatory bowel disease (IBD) is an inflammatory disorder of the intestine that affects an estimated 329 per 100,000 people in the United States and is increasing in incidence within a number of cultures worldwide. Likely due to its incompletely understood pathophysiology and etiology, the standard treatments for IBD are only efficacious in subsets of patients and often do not induce lasting remission. As a result, novel therapies are needed. The success of anti–tumor necrosis factor-α treatment in a subset of patients with IBD demonstrated that therapy targeting a single cytokine could be efficacious in IBD, and clinical trials investigating the blockade of a variety of cytokines have commenced. Interleukin (IL) 27 is a relatively recently discovered type I cytokine with established roles in infectious disease, autoimmunity, and cancer in a variety of organs. IL-27 was identified as a candidate gene for IBD, and a number of studies in mouse models of IBD have demonstrated that IL-27 therapy is protective. However, in contrast to these investigations, genetic deletion of the IL-27 receptor has been shown to be protective in some mouse models of IBD. The purpose of this review is to highlight the recent literature investigating the role of IL-27 in IBD and to discuss the possible explanations for the sometimes conflicting results of these studies. Evidence supporting IL-27 therapy as a treatment for IBD will also be discussed.