SummaryMedium-and heavy-duty vehicles (MHDVs) comprise only a small fraction of vehicles on the road but disproportionately contribute to greenhouse gas emissions and air pollution from the transportation sector. Given the large variety of vehicle types—ranging from heavy-duty pickup trucks and box trucks to full-size buses and Class 8 tractor semi-trailers—and applications, multiple technologies offer opportunities to decarbonize MHDVs including battery-electric vehicles, hydrogen fuel cell vehicles, and sustainable liquid fuels. Here we provide an overview of the status, opportunities, challenges, and uncertainties for these competing—and potentially complementary—technologies, including consideration of supporting infrastructure and prospects for future success. We find a bright outlook for zero-emission vehicles and discuss remaining barriers and uncertainties around fleet decisions and changes to vehicle operation, infrastructure, manufacturing, and future fuel and technology trends that can be informed through analysis.