Organophosphate acid anhydrases (OPA anhydrases) are a diverse and widespread group of enzymes that are able to hydrolyze the potent organophosphate acetylcholinesterase inhibitors 0,0-diisopropylphospho-fluoridate (DFP) and 0-1,2,2-trimethylpropylmethylphosphono-fluoridate (soman). Five enzymatic activities have been identified in the ubiquitous freshwater protozoan, Tetrahymena thermophila. In some cases the activities share characteristics of both the squid-type and Mazur-type DFPases. A chromogenic substrate related to parathion, 4-nitrophenylethylphenyl(pheny)phosphinate (NPEPP), is hydrolyzed by Tetrahymena DFPase-1 and DFPase-2 and by the Mazur-type DFPase from hog kidney. The close DFP analog N,N′-diisopropyldiamidofluoridate (Mipafox) is a potent inhibitor of the Tetrahymena-DFPases. OPA anhydrase activities have also been found in the clam, Rangia cuneata. Three groups of activity can be identified at molecular weights of 20 000 to 30 000 daltons (D), 45 000 to 50 000 D, and 70 000 to 100 000 D. The higher molecular weight activity resembles a Mazur-type DFPase in that it hydrolyzes soman faster than DFP, is Mn²⁺ stimulated, and hydrolyzes NPEPP. The lower molecular weight activity is in the range of the squid-type DFPase. An enzymatic activity that hydrolyzes Mipafox is apparent at a molecular weight of 130 000 D. A hypothesis is presented that the wide variety of OPA anhydrases is in part due to the need for the metabolism of a wide variety of naturally occurring organophosphates and halogenated organics.