Carbon monoxide is an important one-carbon source and can be incorporated in complex molecules via various transition-metal-catalyzed carbonylation reactions. In particular, palladium-catalyzed carbonylation reactions have found broad application in total synthesis of natural products. Examples are presented in this Synopsis to highlight recent progress in this area, including our own work in macrolide and spirocyclic molecule synthesis. In these selected cases, carbon monoxide functions as a one-carbon linchpin to facilitate building structural complexity and improving synthetic efficiency.