Although wildfire has been central to the ecological dynamics of Interior Alaska for 5000 yr, the role of humans in this dynamic is not well known. As a multidisciplinary research team, together with native community partners, we analyzed patterns of human-fire interaction in two contiguous areas of Interior Alaska occupied by different Athabaskan groups. The Koyukon in the western Interior considered fire a destructive force and had no recollection or oral history of using fire for landscape management. Low lightning-strike density and moist climate constrained the effects of lightning fires, and a subsistence dependence on salmon, a relatively predictable resource, resulted in a trilocal residency pattern. In this environment the occurrence of wildfire would have negatively impacted territorial use and the exploitation of wildlife resources. In contrast, the Gwich'in of the eastern Interior actively used fires to manage the landscape. The Gwich'in territory experienced a higher lightning-strike density and a corresponding increase in wildfire activity. The Gwich'in showed greater mobility in hunting moose and caribou, their less spatially predictable subsistence resources, which enabled them to avoid and/or target a range of habitats affected by wildfires. The contrasts between these two neighboring Athabaskan groups indicate different uses and views of wildfire that are derived from their cultural adaptation to local biophysical and ecological settings. These findings call into question the commonly held view that native peoples of North America pervasively and near universally modified landscapes through the use of fire.