Beijing, as a representative megacity in China, is experiencing some of the most severe air pollution episodes in the world, and its fast urbanization has led to substantial urban and peri-urban disparities in both health status and air quality. Uncertainties remain regarding the possible causal links between individual air pollutants and health outcomes, with spatial comparative investigations of these links lacking, particularly in developing megacities. In light of this challenge, Effects of AIR pollution on cardiopuLmonary disEaSe in urban and peri-urban reSidents in Beijing (AIRLESS) was initiated, with the aim of addressing the complex issue of relating multi-pollutant exposure to cardiopulmonary outcomes. This paper presents the novel methodological framework employed in the project, namely (1) the deployment of two panel studies from established cohorts in urban and peri-urban Beijing, with different exposure settings regarding pollution levels and diverse sources; (2) the collection of detailed measurements and biomarkers of participants from a nested case (hypertensive) and control (healthy) study setting; (3) the assessment of indoor and personal exposure to multiple gaseous pollutants and particulate matter at unprecedented spatial and temporal resolution with validated novel sensor technologies; (4) the assessment of ambient air pollution levels in a large-scale field campaign, particularly the chemical composition of particulate matter. Preliminary results showed that there is a large difference between ambient and personal air pollution levels, and the differences varied between seasons and locations. These large differences were reflected on the different health responses between the two panels.