Recent translational studies have provided new insights into the pathogenesis of pediatric-onset inflammatory bowel disease. Registry studies have identified distinct clinical phenotypes with increasing age of onset; this has led to a revision of the clinical phenotyping system, now termed the Paris classification system. It is recognized that there are infantile (age, <1 years), very early onset (VEO) (age, 1–10 years), and early onset (age, 10–17 years) forms of disease. Rare genetic mutations affecting antimicrobial and anti-inflammatory pathways have been discovered in infantile and VEO forms, although genetic pathways identified in early onset disease have been similar to adult-onset inflammatory bowel disease. An increasing incidence in the infantile and VEO forms has suggested an important environmental influence. This is likely ultimately expressed through alterations in the enteric flora (dysbiosis) and dysregulated immune responses to the flora, which are recognized as a critical trigger for mucosal inflammation. These data should ultimately guide new pathogenic models of disease, which will inform both therapy in individual patients and disease prevention in their at-risk family members.