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Although concentrations of ambient air pollution continue to decline in high-income regions, epidemiological studies document adverse health effects at levels below current standards in many countries. The Health Effects Institute (HEI) recently completed a comprehensive research initiative to investigate the health effects of long-term exposure to low levels of air pollution in the United States (U.S.), Canada, and Europe. We provide an overview and synthesis of the results of this initiative along with other key research, the strengths and limitations of the research, and remaining research needs. The three studies funded through the HEI initiative estimated the effects of long-term ambient exposure to fine particulate matter (PM 2.5 ), nitrogen dioxide, ozone, and other pollutants on a broad range of health outcomes, including cause-specific mortality and cardiovascular and respiratory morbidity. To ensure high quality research and comparability across studies, HEI worked actively with the study teams and engaged independent expert panels for project oversight and review. All three studies documented positive associations between mortality and exposure to PM 2.5 below the U.S. National Ambient Air Quality Standards and current and proposed European Union limit values. Furthermore, the studies observed nonthreshold linear (U.S.), or supra-linear (Canada and Europe) exposure-response functions for PM 2.5 and mortality. Heterogeneity was found in both the magnitude and shape of this association within and across studies. Strengths of the studies included the large populations (7-69 million), state-of-the-art exposure assessment methods, and thorough statistical analyses that applied novel methods. Future work is needed to better understand potential sources of heterogeneity in the findings across studies and regions. Other areas of future work include the changing and evolving nature of PM components and sources, including wildfires, and the role of indoor environments. This research initiative provided important new evidence of the adverse effects of long-term exposures to low levels of air pollution at and below current standards, suggesting that further reductions could yield larger benefits than previously anticipated.