Buildings consume more than one-third of the world’s primary energy. Reducing energy use and greenhouse-gas emissions in the buildings sector through energy conservation and efficiency improvements constitutes a key strategy for achieving global energy and environmental goals. Building performance simulation has been increasingly used as a tool for designing, operating and retrofitting buildings to save energy and utility costs. However, opportunities remain for researchers, software developers, practitioners and policymakers to maximize the value of building performance simulation in the design and operation of low energy buildings and communities that leverage interdisciplinary approaches to integrate humans, buildings, and the power grid at a large scale. This paper presents ten challenges that highlight some of the most important issues in building performance simulation, covering the full building life cycle and a wide range of modeling scales. The formulation and discussion of each challenge aims to provide insights into the state-of-the-art and future research opportunities for each topic, and to inspire new questions from young researchers in this field.