A high-performance cleanroom should provide efficient energy performance in addition to effective contamination control. Energy-efficient designs can yield capital and operational cost savings, and can be part of a strategy to improve productivity in the cleanroom industry. Based upon in-situ measurement data from ISO Class 5 cleanrooms, this article discusses key factors affecting cleanroom air system performance and benefits of efficient airflow design in cleanrooms. Cleanroom HVAC systems used in the semiconductor, pharmaceutical, and healthcare industries are very energy intensive, requiring large volumes of cleaned air to remove or dilute contaminants for satisfactory operations. There is a tendency, however, to design excessive airflow rates into cleanroom HVAC systems, due to factors such as design conservatism, lack of thorough understanding of airflow requirements, concerns about cleanliness reliability, and potential design and operational liabilities.