The abundant class of bacterial Hfq-associated small regulatory RNAs (sRNAs) parallels animal microRNAs in their ability to control multiple genes at the posttranscriptional level by short and imperfect base pairing. In contrast to the universal length and seed pairing mechanism of microRNAs, the sRNAs are heterogeneous in size and structure, and how they regulate multiple targets is not well understood. This paper provides evidence that a 5′ located sRNA domain is a critical element for the control of a large posttranscriptional regulon. We show that the conserved 5′ end of RybB sRNA recognizes multiple mRNAs of Salmonella outer membrane proteins by ≥7-bp Watson–Crick pairing. When fused to an unrelated sRNA, the 5′ domain is sufficient to guide target mRNA degradation and maintain σ ^E -dependent envelope homeostasis. RybB sites in mRNAs are often conserved and flanked by 3′ adenosine. They are found in a wide sequence window ranging from the upstream untranslated region to the deep coding sequence, indicating that some targets might be repressed at the level of translation, whereas others are repressed primarily by mRNA destabilization. Autonomous 5′ domains seem more common in sRNAs than appreciated and might improve the design of synthetic RNA regulators.