AbstractHfq is the bacterial orthologue of the eukaryotic (L)Sm family of proteins found across all domains of life and potentially an ancient protein, but it has not been found in all phyletic lines. A careful search successfully identified a distant hfq orthologue in the cyanobacteria leaving the actinobacteria as the major phylum with no known hfq orthologue. A search for hfq in actinobacteria, using domain enhanced searching (DELTA-BLAST) with cyanobacterial hfq, identified a conserved actinobacterial specific protein as remotely homologous. Structural homology modelling using profile matching to fold libraries andab initio3D structure determination supports this prediction and suggests module shuffling in the evolution of the actinobacterial hfq. Our results provide the basis to explore this prediction, and exploit it, across diverse taxa with potentially important post-transcriptional regulatory effects in virulence, antibiotic production and interactions in human microbiomes. However, the role of hfq in gram positive bacteria has remained elusive and experimental verification will be challenging.