Translation termination requires codon-dependent polypeptide release factors. The mechanism of stop codon recognition by release factors is unknown and holds considerable interest since it entails protein-RNA recognition rather than the well-understood mRNA-tRNA interaction in codon-anticodon pairing. Bacteria have two codon-specific release factors and our picture of prokaryotic translation is changing because a third factor, which stimulates the other two, has now been found. Moreover, a highly conserved eukaryotic protein family possessing properties of polypeptide release factor has now been sought. This review summarizes our current understanding of the structural and functional organization of release factors as well as our recent findings of highly conserved structural motifs in bacterial and eukaryotic polypeptide release factors.