This paper presents the key factors methodology that supports energy managers in determining the optimal building operation strategy in relation to both energy consumption and thermal comfort. The methodology is supported by the utilization of calibrated building energy simulation models that match measured data gathered by an extensive measurement framework Building management systems, do not allow energy managers to test the impact of changes in control settings of energy systems on energy consumption and thermal comfort. The proposed methodology and prototype tool chain enables energy managers to virtually develop and test the impact of proposed changes to the control settings in the building energy systems prior to their implementation in the physical building. The paper outlines the proposed methodology defining the underpinning concepts and illustrating the performance metrics required to capture the effect of different building operation strategies. A case study is discussed to demonstrate the application of the methodology. (C) 2012 Elsevier B.V. All rights reserved.