In 1938, Hopkins and coworkers (1, 2) showed that succinic dehydrogenase could be inactivated by oxidized glutathione (GSSG) and could be reactivated by reduced glutathione (GSH). They interpreted these results to mean that the active enzyme requires i n t a c t --S H groups and that when these are converted to the --S --S --form of the enzyme, the dehydrogenase is inactivated. Any assumption that the functioning of the enzyme involved an oscillation between the SH and the --S---S---form of the enzyme seemed to be definitely eliminated, however, by the fact that the --S --S --form could not be reduced by succinate. Thus the function of the SH group in succinic dehydrogenase has remained an unsolved problem.Although many proteins contain SH groups, very little is known about the structural relationship of the SH group to the rest of the molecule. Even in the case of egg albumin, in which the SH groups have received the most careful study, the mechanism by which the SH groups of native egg albumin are shielded from some sulfhydryl reagents and not from others remains obscure (3). In the case of succinic dehydrogenase, the presumptive SH group (1, 2) is associated with function, and the reaction of the protein with sulfhydryl reagents should be demonstrable on the basis of determinations of the amount of active enzyme remaining. Furthermore, since it is an oxidative enzyme, the measurement of oxygen uptake makes possible a continuous appraisal of the amount of active enzyme at any given moment. We have previously established the test conditions for the measurement of the activity of this enzyme (4, 5). The rate of oxygen uptake is a valid measure of succinic dehydrogenase activity in this system since cytochrome c and cytochrome oxidase, which are needed to complete the reaction with oxygen, are present in excess. The activity of the enzyme is so great under the proper conditions that the extraneous matter present in the enzyme preparation does not interfere with the study of the reaction.At present, inhibitor studies appear to constitute the only available means of establishing the presence of SH groups in succinic dehydrogenase and of determining their r61e in the function of the enzyme.