The low-cost and abundant supply of shale gas in the United States has increased the interest in using natural gas for transportation. We compare the life cycle greenhouse gas (GHG) emissions from different natural gas pathways for medium and heavy-duty vehicles (MHDVs). For Class 8 tractor-trailers and refuse trucks, none of the natural gas pathways provide emissions reductions per unit of freight-distance moved compared to diesel trucks. When compared to the petroleum-based fuels currently used in these vehicles, CNG and centrally produced LNG increase emissions by 0-3% and 2-13%, respectively, for Class 8 trucks. Battery electric vehicles (BEVs) powered with natural gas-produced electricity are the only fuel-technology combination that achieves emission reductions for Class 8 transit buses (31% reduction compared to the petroleum-fueled vehicles). For non-Class 8 trucks (pick-up trucks, parcel delivery trucks, and box trucks), BEVs reduce emissions significantly (31-40%) compared to their diesel or gasoline counterparts. CNG and propane achieve relatively smaller emissions reductions (0-6% and 19%, respectively, compared to the petroleum-based fuels), while other natural gas pathways increase emissions for non-Class 8 MHDVs. While using natural gas to fuel electric vehicles could achieve large emission reductions for medium-duty trucks, the results suggest there are no great opportunities to achieve large emission reductions for Class 8 trucks through natural gas pathways with current technologies. There are strategies to reduce the carbon footprint of using natural gas for MHDVs, ranging from increasing vehicle fuel efficiency, reducing life cycle methane leakage rate, to achieving the same payloads and cargo volumes as conventional diesel trucks.