Inflammatory bowel disease (IBD) encompasses a heterogeneous group of autoinflammatory disorders of the gastrointestinal tract. Collectively, IBD afflicts over one million Americans and is one of only a few diseases with rising incidence. IBD patients suffer from a number of symptoms and sequelae including severe abdominal pain, bloody diarrhea, anemia, malnutrition, failure to thrive, colonic fistulas and strictures, and a significantly increased risk for the development of colonic cancer. While the etiology of IBD is enigmatic, clinical sequencing has brought to light the important role of the innate immune system in the pathology of IBD. Recently, sequencing of pediatric IBD patients has uncovered mutations to the X-linked inhibitor of apoptosis (XIAP) protein. The work presented here highlights the molecular role of XIAP mutation in mediating innate immune signaling defects that contribute to the pathogenesis of inflammatory bowel disease. It confirms the cognate kinase of XIAP, RIPK2 as a unique pharmacologic target using a synthetic approach. It identifies the consequence of patient-sourced XIAP mutations, which show both loss of NOD2 signaling and cell death susceptibility. Lastly, it outlines a set of experiments to identify novel XIAP-regulated pathways and features to continue unraveling XIAP’s role in IBD. Collectively, this work provides not only new insight into the pathogenesis of XIAP-driven IBD, but also provides a platform for future efforts aimed at investigation into mechanisms of inflammatory disease driven by protein mutation and at pharmacologic discovery for disease intervention.