The intestinal microbiota, which is composed of bacteria, viruses, and micro-eukaryotes, acts as an accessory organ system with distinct functions along the intestinal tract that are critical for health. This presentation focuses on how the microbiota drives intestinal disease through alterations in microbial community architecture, disruption of the mucosal barrier, modulation of innate and adaptive immunity, and dysfunction of the enteric nervous system. Inflammatory bowel disease and Type 1 diabetes are used as a model systems to understand these microbial-driven pathologies. Fecal microbiota transplantation (FMT) from healthy donor to patient is a treatment for microbiome-associated diseases. Using an ongoing clinical experiment, the treatment of recurrent Clostridium difficile infection, to uncover the rules of engraftment in humans and discuss approaches to micro biome therapeutics.