Predicting the performance of natural ventilation is difficult, especially for the large scale naturally ventilated buildings, because of the lack of accurate and efficient prediction tools. This paper presents a strategy, integrating a multi-zone model and computational fluid dynamics (CFD), to improve natural ventilation prediction and design. Large openings and atrium are broadly used in naturally ventilated buildings to promote buoyancy force and optimize air movement. How to properly deal with large openings and atrium is discussed and compared in this paper. Coupling strategies for dealing with velocity and pressure boundary conditions are examined and compared as well.