The mechanism for carbon-carbon bond formation used in the biosynthesis of natural products such as fatty acids and polyketides is a decarboxylating Claisen condensation. The enzymes that catalyze this reaction in various bacterial systems, collectively referred to as condensing enzymes, have been intensively studied in the past several decades, and members of the family have been crystallized. The condensing enzymes share a common 3-dimensional fold, first described for the biosynthetic thiolase I that catalyzes a non-decarboxylating Claisen condensation, although they share little similarity at the amino acid level. Their active sites, however, possess significant similarities. The initiation condensing enzymes use CoA primers and possess a catalytic triad of Cys, His, Asn; and the elongating condensing enzymes that exclusively use ACP thioesters have a triad of Cys, His, His. These active site differences affect the sensitivity of the respective enzymes to the antibiotics thiolactomycin and cerulenin. Different reaction mechanisms have been proposed for the condensing enzymes. This review covers the recent structural and mechanistic data to see if a unifying hypothesis for the reaction mechanism catalyzed by this important family of enzymes can be established.