Substantial uncertainty surrounds how forest ecosystems will respond to the simultaneous impacts of multiple global change drivers. Long-term forest dynamics are sensitive to changes in tree mortality rates; however, we lack an understanding of the relative importance of the factors that affect tree mortality across different spatial and temporal scales. We used the US Forest Service Forest Inventory and Analysis database to evaluate the drivers of tree mortality for eastern temperate forest at the individual-level across spatial scales from tree to landscape to region. We investigated 13 covariates in four categories: climate, air pollutants, topography, and stand characteristics. Overall, we found that tree mortality was most sensitive to stand characteristics and air pollutants. Different functional groups also varied considerably in their sensitivity to environmental drivers. This research highlights the importance of considering the interactions among multiple global change agents in shaping forest ecosystems.