This Cyber-Physical Systems project designs and evaluates a foundational information substrate for efficient, agile, model-driven, human-centered building systems. The approach is to develop software-defined buildings, to shatter existing stovepipe architectures, dramatically reduce the effort to add new functions and applications without forklift upgrades, and expand communications and control capabilities beyond a single stand-alone building to enable groups of buildings to behave cooperatively and in cooperation with the energy grid. We investigate how such Software-Defined Buildings can be founded on a flexible, multi-service and open Building Integrated Operating System (BIOS) that allows applications to run reliably in safe, sandboxed environments. It supports sensor and actuator access, access management, metadata, archiving, and discovery, as well as multiple simultaneously executing programs. Building operators retain supervisory management, controlling application separation physically (access different controls), temporally (change controls at different times), informationally (what information leaves the building), and logically (what actions or sequences thereof are allowable). We construct, deploy, and demonstrate the capabilities of a prototype BIOS in the context of university, residential buildings and closely related industrial processes. Making buildings more efficient, while keeping occupants comfortable, productive, and healthy, is critical to our economy and health. Transforming buildings into agile, human centered cyber-physical systems eliminates waste, while allowing them to be a proactive resource on the electric grid with zero emission renewable supplies. And by providing greater value from the same physical plant, the SDB approach can move beyond cost-to-build and cost-to-operate metrics to broader return-on-investment for new extendable future-proof technologies.