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Puf domain proteins bind specific sequences in mRNAs to regulate their translation or stability, or both. Neither the mechanism of their action nor the identities of targeted mRNAs have been well defined. Recent work suggests that Puf proteins generally act by recruiting Pop2, a deadenylation enzyme that is part of a large complex. Recent work from a separate group defines a subset of the Drosophila transcriptome that is bound by the fly Puf protein, Pumilio. Together, these papers substantially increase our understanding of the biology of the Puf family of mRNA regulators.