Ketoacyl reductases (KRs), hydroxyacyl dehydratases (HDs), and enoyl reductases (ERs) are part of the fatty acid/polyketide synthesis cycle. They are known as acyl dehydrogenases, enoyl hydratases, and hydroxyacyl dehydrogenases, respectively, when catalyzing their reverse reactions. Earlier, we classified these enzymes into four KR, eight HD, and five ER families by statistical criteria. Members of all four KR families and three ER families have Rossmann folds, while five HD family members have HotDog folds. This suggests that those proteins with the same folds in different families may be distantly related, and therefore in clans, even though their amino acid sequences may not be homologous. We have now defined two clans containing three of the four KR families and two of the eight HD families, using manual and statistical tests. One of the ER families is related to the KR clan.