The microbial residents of the human gut are a major factor in the development and lifelong maintenance of health. The gut microbiota differs to a large degree from person to person and has an important influence on health and disease due to its interaction with the human immune system. Its overall composition and microbial ecology have been implicated in many autoimmune diseases, and it represents a particularly important area for translational research as a new target for diagnostics and therapeutics in complex inflammatory conditions. Determining the biomolecular mechanisms by which altered microbial communities contribute to human disease will be an important outcome of current functional studies of the human microbiome. In this review, we discuss functional profiling of the human microbiome using metagenomic and metatranscriptomic approaches, focusing on the implications for inflammatory conditions such as inflammatory bowel disease and rheumatoid arthritis. Common themes in gut microbial ecology have emerged among these diverse diseases, but they have not yet been linked to targetable mechanisms such as microbial gene and genome composition, pathway and transcript activity, and metabolism. Combining these microbial activities with host gene, transcript and metabolic information will be necessary to understand how and why these complex interacting systems are altered in disease-associated inflammation.