Abstract Route 66 is among the most famous American highways of the middle twentieth century. A portion of the original Route 66 runs through southwestern Missouri, southeastern Kansas, and northeastern Oklahoma. This section of the road was intimately linked to the Tri-state region’s economic geology, namely mining lead and zinc as well as producing the fossil fuels—coal and natural gas—to smelt the ore. Mining began in the Tri-state district in the mid-nineteenth century and continued into the late twentieth century. An economic boom led to regional population growth and contributed to national development, but no environmental regulations existed during this period. The legacy of mining includes severe pollution, ruined communities, serious human-health issues, and devastated landscapes. Efforts now focus on protecting human health, reclamation of mined land, and remediation of water resources, led by federal and state agencies as well as universities and non-governmental organizations.