Energy models of existing buildings are unreliable unless calibrated so that they correlate well with actual energy usage. Manual tuning requires a skilled professional, is prohibitively expensive for buildings below 50,000 ft 2 , imperfect, non-repeatable, and not scalable to the dozens of sensor channels that smart meters, smart appliances, and sensors are making available. A scalable, automated methodology is needed to quickly, intelligently calibrate building energy models to all available data, increase the usefulness of those models, and facilitate speed-and-scale penetration of simulation-enhanced capabilities into the marketplace for actualized energy savings. The "Autotune" project is a novel, model-agnostic methodology that leverages supercomputing, large simulation ensembles, and big data mining with multiple machine learning algorithms to allow automatic calibration of simulations that match measured experimental data in a way that is deployable on commodity hardware. This paper shares several methodologies employed to reduce the combinatorial complexity to a computationally tractable search problem for hundreds of input parameters. Accuracy metrics are provided that quantify model error to measured data from a highly instrumented, emulated-occupancy research home.