Genomes to Life (GTL), the U.S. Department of Energy Office of Science?s systems biology program, focuses on environmental microbiology. Over the next 10 to 20 years, GTL?s key goal is to understand the life processes of thousands of microbes and microbial systems in their native environments. This focus demands that we address huge gaps in knowledge, technology, computing, data capture and analysis, and systems-level integration. Distinguishing features include (1) strategies for unprecedented, comprehensive, and high-throughput data collection; (2) advanced computing, mathematics, algorithms, and data-management technologies; (3) a focus on potential microbial capabilities to help solve energy and environmental challenges; and (4) new research and management models that link production-scale systems biology facilities in an accessible environment. This unprecedented opportunity to provide the scientific foundation for solving urgent problems in energy, global climate change, and environmental cleanup demands that we take bold steps to achieve a much faster, more efficient pace of biological discovery.