A number of drugs act by inhibition of a specific target enzyme, thereby interfering with the synthesis of a key metabolite. When a specific enzyme inhibitor is applied to a functioning metabolic pathway, the substrate will accumulate and the inhibition will be counteracted, a phenomenon known as metabolic resistance. The work described in this report delineates the circumstances which accentuate, and those which suppress, metabolic resistance. By computer simulation it is shown that the effect of an inhibitor is less pronounced when the target enzyme is remote from the reaction which produces the key metabolite, separated from it by a large pool of intermediates, or separated by an enzyme which is nearly saturated with its substrate. Further, it is shown that noncompetitive, uncompetitive, or irreversible inhibitors are more effective than competitive inhibitors. Finally, enzymes immediately following a branch point and those which form part of a cycle are the least likely to exhibit metabolic resistance. These considerations are encapsulated in six rules for the selection of preferred enzyme targets for drug action.