The systems biology revolution is proceeding along multiple pathways as different science agencies and the private sector have adopted strategies suited to their particular needs and cultures. To meet this challenge, the U.S. Department of Energy has developed the Genomes to Life (GTL) program. A central focus of GTL is environmental microbial biology as a way to approach global environmental problems, and its key goal is to achieve, over the next 10 to 20 years, a basic understanding of thousands of microbes and microbial systems in their native environments. This focus demands that we address huge gaps in knowledge, technology, computing, data storage and manipulation, and systems-level integration.