The Haloalkanoate Dehalogenase Superfamily (HADSF) ranks high among Nature's protein catalysts with over 19,000 homologous sequences reported in gene databanks. Numerous proteins from the HADSF are found in each organism (29 in E. coli and 183 in humans, for example) where they perform a diverse collection of physiological functions in primary and secondary metabolism, membrane transport, signal transduction, and nucleic-acid repair.The wide range of function and corresponding substrate range is suggestive of the versatility of the HADSF fold, and the importance of this line of catalyst to cellular function. Thesuccessful adaptation to various substrates stems from the “modular” design of the scaffold, with a catalytic site conferred by the core domain spatially distinct from the substrate binding site conferred by the cap domain. Novel chemistries are afforded by the differential usage of the metal/solvent binding loop, the acid/base catalyst, conformational coupling to ligand binding, and accessory residues from the capping domain. The evolution of new chemistries and substrate specificities will be discussed in the context of atomic structural and functional information obtained by X-ray crystallography, kinetics and SAXS.