Synthetic biology promises to lead the way to a sustainable manufacturing sector. If the thousands of chemicals derived from petroleum and natural gas — including fuels, plastics and industrial chemicals — could be produced instead with microbes, the annual savings in global greenhouse gas emissions would be substantial. Most manufacturing processes developed by synthetic biology approaches have not been fully carbon neutral, in part because they rely on sugar feedstocks. An important new study in Nature Biotechnology by Liew et al.1 describes a strategy for carbon-negative manufacturing of chemicals at large scale by harnessing a class of autotrophic bacteria called acetogens. These bacteria can live on one-carbon molecules — including the greenhouse gas CO2 — and convert them into more-complex, organic molecules. But acetogens have proved extremely difficult to genetically engineer for the synthesis of non-native products. Liew et al. describe methods to overcome previous technical hurdles, achieving carbon-negative production of the non-native chemicals acetone and isopropanol (IPA) at industrially relevant efficiency, selectivity and scale. The study provides a roadmap for broadening the range of molecules that can be manufactured sustainably from waste and biomass feedstocks.