Mitigating climate change is a key driver for the development of sustainable and CO2-neutral production processes. In this regard, connecting carbon capture and utilization processes to derive microbial C1 fermentation substrates from CO2 is highly promising. This strategy uses methylotrophic microbes to unlock next-generation processes, converting CO2-derived methanol. Synthetic biology approaches in particular can empower synthetic methylotrophs to produce a variety of commodity chemicals. We believe that yeasts have outstanding potential for this purpose, because they are able to separate toxic intermediates and metabolic reactions in organelles. This compartmentalization can be harnessed to design superior synthetic methylotrophs, capable of utilizing methanol and other hitherto largely disregarded C1 compounds, thus supporting the establishment of a future circular economy.