A shortage of rhesus monkeys for use in drug toxicity studies has made it necessary to search for a potential replacement species in the event that one should be needed in the near future. To this end, 14 parameters of drug metabolism in hepatic microsomal and soluble fractions were examined in preparations from adult male and female rhesus monkeys, squirrel monkeys, Hanford miniature pigs, common tree shrews, and Sprague-Dawley rats. Model substrates were utilized and comparisons were made on a quantitative basis. All species tested demonstrated activity in all but one test assay and all showed some similarity to the rhesus. None of the species, however, was totally comparable to the rhesus in drug-metabolizing ability. The squirrel monkey showed the least similarity to the rhesus and the miniature pig was the most similar. With the exception of the expected differences in the rat, the tree shrew demonstrated the only sex difference in drug metabolism, the enzyme activities of females being higher than the male in several pathways. The data suggest that any of the four species tested could be a suitable replacement for the rhesus in studies of drug metabolism in vitro.