Malonyl-CoA is one of the fundamental building blocks for the synthesis of industrially or pharmaceutically important chemicals, but its biosynthesis via the innate acetyl-CoA carboxylation pathway remains slow and inefficient. Now, an artificial non-carboxylative malonyl-CoA biosynthetic pathway has been developed, significantly enhancing malonyl-CoA supply by boosting carbon and energy efficiency while sidestepping the inhibitions by host cell regulations.