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Uncultured microorganisms comprise the majority of the planet's biological diversity. In many environments, as many as 99% of the microorganisms cannot be cultured by standard techniques, and the uncultured fraction includes diverse organisms that are only distantly related to the cultured ones. Therefore, culture-independent methods are essential to understand the genetic diversity, population structure, and ecological roles of the majority of microorganisms. Recently,new techniques for studying microbial communities, collectively called metagenomics, have been developed to overcome the limitations of culturing. This review assesses the potential of metagenomic techniques to analyze the relative abundance of microbial species under varying human environmental conditions and to discover infectious causes of unexplained human diseases.