Inflammatory bowel diseases (IBD) are chronic, progressive diseases characterized by aberrant immune responses to environmental and gut microbial triggers in genetically susceptible hosts. Compelling clinical, genetic, and experimental data support the role of gut microbes in causing and sustaining these diseases. In addition, our concepts of IBD have changed dramatically through advances in technologies and experimental and clinical model systems. Despite this, the study of microbes in human IBD remains descriptive and some of the most basic questions about the role of the gut microbiota in causing and perpetuating disease remain unanswered. The next phase of investigations of the gut microbiome in IBD should be guided by specific biological questions relevant to clinical observation and the natural history of the diseases. This approach will be essential for the eventual development of microbial, genetic, and biological metrics useful for individualized assessment of risk and improvement of clinical outcomes in IBD.