These authors show how synthetic small RNAs (sRNAs) can be used to improve bacterial metabolic engineering. First, they developed an efficient approach to identifying target genes for which downregulation increases the production of a desired compound. They designed synthetic sRNAs against candidate genes and used these to identify combinations of strains and repressed targets with the highest levels of production. They also showed that engineered sRNAs can be used to fine-tune, rather than to knock out, target gene expression to generate better-performing strains.