A large region of two distinct yeast histone deacetylases, RPD3 and HDA1, is highly homologous to several prokaryotic enzymes that catalyze reactions involving various acetylated substrates. Proteins sharing this homology domain are found also in many higher eukaryotes and they all appear to be related to the RPD3 family of histone deacetylases. In each member of the family, the `prokaryotic homology' domain covers almost two thirds of the protein, with the remaining portion containing the most divergent sequences. These sequences are located at the C‐terminal region allowing for a clear definition of variants. Since the involvement of deacetylase members in different distinct regulatory complexes is now well established, the above observation suggests that the C‐terminal domain may confer specificity to different members of the family. The RPD3 histone deacetylases thus appear as members of a family with a large conserved domain involved in enzymatic activity targeted to a short C‐terminal domain, which probably confers functional specificity. The potential for deacetylases to be involved in multiple regulatory pathways provides an attractive counterpoint to the role of multiple histone acetyltransferases as coactivators.