Over the course of our lives, humans are colonized by a tremendous diversity of commensal microbes, which comprise the human microbiome. The collective genetic potential (metagenome) of the human microbiome is orders of magnitude more than the human genome, and it profoundly affects human health and disease in ways we are only beginning to understand. Advances in computing and high-throughput sequencing have enabled population-level surveys such as MetaHIT and the recently released Human Microbiome Project, detailed investigations of the microbiome in human disease, and mechanistic studies employing gnotobiotic model organisms. The resulting knowledge of human microbiome composition, function, and range of variation across multiple body sites has begun to assemble a rich picture of commensal host-microbe and microbe-microbe interactions as well as their roles in human health and disease and their potential as diagnostic and therapeutic tools.