The association between short-term exposure to extreme weather events and health has been well established. In addition, there is a large body of epidemiological literature on the short and long-term effects of ambient exposure to PM 2.5 . We hypothesize that the health impact associated with exposure to air pollution and weather is larger than the risk estimated based on the health effects of air pollution and weather alone. Not much work has been done to estimate the acute and chronic effects associated with simultaneous exposure to multiple environmental agents such as weather and particulate matter. In this editorial we highlight challenges in addressing these interactions. Around the globe, exposure to weather parameters, composition of gaseous and particulate air pollution, and the ventilation rates vary by season. Furthermore, weather and pollution mixtures exhibit different exposure-response function and act through different pathophysiological mechanisms. The synergistic analysis of ambient air pollution and weather require studies collecting appropriate data and advancing methodological approaches. Due to large variation in space and time, carefully designed multi-center studies will be important to address these challenges and provide novel stimuli for promoting measures to slow climate change and improve air pollution in urban areas and in cities around the world.