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The DOE Systems Biology Knowledgebase (KBase), a resource led by Lawrence Berkeley National Laboratory in collaboration with Argonne, Oakridge and Brookhaven National Laboratories, aims to provide the environment needed to address the grand challenges of systems biology: predicting and ultimately designing biological function. KBase enables secure sharing of data, tools, and conclusions in a unified, extensible system that allows researchers to collaboratively generate, test, and share hypotheses about molecular and cellular functions; perform large-scale analyses on scalable computing infrastructure; and combine multiple lines of evidence to model with increasing accuracy plant and microbial physiology and community dynamics. The system is designed to enable efficient cycles of model-driven experimental design and refinement to support discoveries of biomolecular function; insights into cellular network operation and organismal adaptation within heterogeneous populations in changeable environments; and organism modifications for effective biodesign of cellular, tissue, and ecosystem behavior for energy and environmental applications.