Recent dramatic and deadly increases in global wildfire activity have increased attention on the causes of wildfires, their consequences, and how risk from wildfire might be mitigated. Here we bring together data on the changing risk and societal burden of wildfire in the United States. We estimate that nearly 50 million homes are currently in the wildland–urban interface in the United States, a number increasing by 1 million houses every 3 y. To illustrate how changes in wildfire activity might affect air pollution and related health outcomes, and how these linkages might guide future science and policy, we develop a statistical model that relates satellite-based fire and smoke data to information from pollution monitoring stations. Using the model, we estimate that wildfires have accounted for up to 25% of PM2.5 (particulate matter with diameter <2.5 μm) in recent years across the United States, and up to half in some Western regions, with spatial patterns in ambient smoke exposure that do not follow traditional socioeconomic pollution exposure gradients. We combine the model with stylized scenarios to show that fuel management interventions could have large health benefits and that future health impacts from climate-change–induced wildfire smoke could approach projected overall increases in temperature-related mortality from climate change—but that both estimates remain uncertain. We use model results to highlight important areas for future research and to draw lessons for policy.