Microbes play fundamental roles in all biology-associated processes on the planet. A powerful new tool in such studies is metagenomics wherein one uses high throughput DNA sequencing methods on DNA isolated directly from environmental samples. Metagenomics has the potential to revolutionize our understanding of the normally hidden yet incredibly important world of microorganisms. However this great potential comes with enormous challenges in the analysis of the sequence data, including (i) the fragmentary nature of sequence data, (ii) the sparse sampling of genomes, populations and communities, and (iii) the unknown phylogenetic diversity and ecological structure of the communities being sampled. We are now working on methodology for analysis of metagenomic data as part of a new collaborative project: Integrating Statistical Evolutionary, and Ecological Approaches to Metagenomics (iSEEM). The iSEEM Project, funded by the Gordon and Betty Moore Foundation, takes an integrated, interdisciplinary approach to metagenomic analysis. We will be working with the Community Cyberinfrastructure for Advanced Marine Microbial Ecology Research and Analysis (CAMERA) to make any methods we develop available to the broader community.