The marine sponge Theonella swinhoei and its uncultivated bacterial endosymbionts are rich sources of bioactive secondary metabolites. Two of these metabolites, polytheonamides A and B, exhibit surprising structural complexity, with 13 of the 19 amino acids that constitute the 48-residue peptides being non-proteinogenic, leading to the general assumption that these peptides were synthesized by a non-ribosomal peptide synthase. However, by mining the sponge metagenome, Freeman et al. identified an operon, probably from a bacterial endosymbiont, that contains an ORF corresponding to an unprocessed polytheonamide precursor, supporting a ribosomal origin for these peptides. The operon also contains six candidate enzymes that probably carry out the 48 different post-translational modifications which help create the functional polytheonamides.