Staufen1 (STAU1)‐mediated mRNA decay (SMD) is an mRNA degradation process in mammalian cells that is mediated by the binding of STAU1 to a STAU1‐binding site (SBS) within the 3′‐untranslated region (3′‐UTR) of target mRNAs. During SMD, STAU1, a double‐stranded (ds) RNA‐binding protein, recognizes dsRNA structures formed either by intramolecular base pairing of 3′‐UTR sequences or by intermolecular base pairing of 3′‐UTR sequences with a long‐noncoding RNA (lncRNA) via partially complementary Alu elements. Recently, STAU2, a paralog of STAU1, has also been reported to mediate SMD. Both STAU1 and STAU2 interact directly with the ATP‐dependent RNA helicase UPF1, a key SMD factor, enhancing its helicase activity to promote effective SMD. Moreover, STAU1 and STAU2 form homodimeric and heterodimeric interactions via domain‐swapping. Because both SMD and the mechanistically related nonsense‐mediated mRNA decay (NMD) employ UPF1; SMD and NMD are competitive pathways. Competition contributes to cellular differentiation processes, such as myogenesis and adipogenesis, placing SMD at the heart of various physiologically important mechanisms. WIREs RNA 2013, 4:423–435. doi: 10.1002/wrna.1168This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms