The common denominator of the numerous data collected from experimental studies on isolated organs, on healthy subjects and on diabetic patients, is a specific effect of sulfonylureas on insulin release in the presence (or absence) of glucose. However, there are significant differences in the capacity of the various chemical preparations active in that respect. There are biochemical data suggesting that the glyburide- and chlorpropamide-type of preparations are affecting sites of the B-cells that are different from both the glucose and the tolbutamide receptors. Thus, glibenclamide seems to be qualitatively different from the older sulfonylureas, being more a potentiator than a stimulator. Therefore, we called this type the representative of 'the second generation' drugs. The extra-B-cell actions of these drugs, predominantly the stimulation of somatostatin and the inhibition of glucagon, are favorably adding to these antidiabetic actions. In clinical therapy, these specific properties make it possible to diagnose and to treat patients successfully who were regarded before as being non-responsive to sulfonylureas and being insulin-dependent. On the basis of blood glucose decreases and C-peptide increases, a specific glibenclamide-glucose-response-test has been described which is a valuable medium for predicting the outcome of oral antidiabetic therapy.