The modeling and simulation of airflow dynamics in buildings has many applications including indoor air quality and ventilation analysis, contaminant dispersion prediction, and the calculation of personal occupant exposure. Multi-zone airflow model software programs provide such capabilities in a manner that is practical for whole building analysis. This research addresses the need for calibration methodologies to improve the prediction accuracy of multi-zone software programs. Of particular interest is accurate modeling of airflow dynamics in response to extraordinary events, i.e. chemical and biological attacks. This research developed and explored a candidate calibration methodology which utilizes tracer gas (e.g., CO2) data. A key concept behind this research was that calibration of airflow models is a highly over-parameterized problem and that some form of model reduction is imperative. Model reduction was achieved by proposing the concept of macro-zones, i.e. groups of rooms that can be combined into one zone for the purposes of predicting or studying dynamic airflow behavior under different types of stimuli. The proposed calibration methodology consists of five steps: (i) develop a "somewhat" realistic or partially calibrated multi-zone model of a building so that the subsequent steps yield meaningful results, (ii) perform an airflow-based sensitivity analysis to determine influential system drivers, (iii) perform a tracer gas-based sensitivity analysis to identify macro-zones for model reduction, (iv) release CO2 in the building and measure tracer gas concentrations in at least one room within each macro-zone (some replication in other rooms is highly desirable) and use these measurements to further calibrate aggregate flow parameters of macro-zone flow elements so as to improve the model fit, and (v) evaluate model adequacy of the updated model based on some metric. The proposed methodology was first evaluated with a synthetic building and subsequently refined using actual measured airflows and CO2 concentrations for a real building. The airflow dynamics of the buildings analyzed were found to be dominated by the HVAC system. In such buildings, rectifying differences between measured and predicted tracer gas behavior should focus on factors impacting room air change rates first and flow parameter assumptions between zones second.