Adding fluorine to small molecules can improve their properties, such as preventing enzymatic breakdown and increasing membrane permeation, but it is hard to add fluorine to natural products. Walker et al. engineered polyketide synthase enzymes, which are normally involved in acetate-based biosynthesis, to incorporate fluoroacetate: the primary product of the only biological fluorination route. In Escherichia coli cells, this process was used as a building block to introduce fluorine substituents in a site-selective manner into polyketide-based natural product scaffolds.