Abstract:Methanol has been considered one of the most important alternative carbon sources for the next-generation biomanufacturing due to its low price, mature production processes, and potential sustainability. Constructing microbial cell factories for methanol to chemical biotransformation has become a research hotspot in the green biomanufacturing industry. Focusing on the microorganisms that can naturally use methanol, we compare them with non-natural cell factories for chemical production from methanol. We discuss the key issues and challenges associated with natural cell factories for chemical production from methanol, summarize recent research progress surrounding these issues, and propose possible solutions to these challenges. This review helps to generate feasible guidelines and research strategies for the modification of natural cell factories for efficient methanol to chemical production in the future.