As humans spend most of their time indoors, indoor air quality (IAQ) significantly impacts their health. In parallel, building ventilation consumes significant energy, contributing to climate change. However, the relationships between the building ventilation, IAQ and its related health effects, and the energy demand are unclear, making the operation and design of ventilation non-optimal. In the initial phase, a thorough assessment of outdoor air pollution was conducted to create a European and global database for air quality simulations. Data were categorized according to urbanization level and proximity to traffic, recognizing the uneven distribution of urban air pollution. Subsequently, methods analogous to those used for typical meteorological years were employed to generate yearly typical air pollution profiles. In the second phase, the research centered on optimizing outdoor air filtration in ventilation systems. Given that filters induce substantial pressure drops in these systems, it was explored whether an enhanced understanding of outdoor air pollution could enable a more energy-efficient fan operation, with results indicating that bypassing the outdoor air filter during periods of low outdoor air pollution levels could save energy from 4% to 14% of fan operation without compromising IAQ. In the third phase, the thesis developed a novel methodology that permits the evaluation of ventilation systems and strategies based on their energy efficiency and the health impacts on building occupants due to air pollution exposure using the Disability-Adjusted Life Years (DALY) methodology. This novel method considers outdoor air pollution more comprehensively and permits a better understanding of the tradeoffs between energy, IAQ, and health, opening the way to a more efficient ventilation design. In the fourth phase, this thesis investigated the energy-saving potential natural ventilation (NV) can achieve in buildings by coupling the comprehensive outdoor air pollution data with building energy simulations. The results revealed that NV can reduce the cooling demand in Europe by 17-100% without increasing the outdoor air pollution penetration. However, restricting the NV use when the outdoor air pollution levels were high limited this energy saving on average by 24%, with this reduction varying significantly within cities. Finally, two case studies were conducted in the framework of this thesis. The first case study refers to the application of an automated window system for NV in a Swiss apartment to demonstrate its efficiency in addressing overheating. The results revealed a relatively minimal reduction in overheating hours. The second case study refers to the effectiveness of user-controlled NV in providing adequate indoor environmental quality with a low energy cost in a dusty environment. The results revealed that well-designed and operated NV achieved high IEQ without excessive energy use. In conclusion, the results revealed that energy savings in the ventilation systems are possible while, in parallel, improving IAQ when the longitudinal outdoor air pollution is considered in the design and operation phases of the building. Designers and building operators can follow the recommendations from this thesis to design and operate buildings more efficiently. Policymakers can benefit from the results to refine the standards and guidelines, contributing to healthier and more sustainable buildings.