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 utilisation of calibrated building energy simulation models that match measured data gathered by an extensive measurement framework. 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 brief case study is discussed to demonstrate the application of the methodology.