The effects of the two groups of oral agents on insulin receptors were studied in several types of cells in tissue culture: MCF-7 human breast cancer cells, IM-9 human lymphocytes, human fibroblasts, and H-35 rat hepatoma cells. In none of these cells did the four sulfonylureas tested, tolbutamide, glibenclamide (glyburide), gliclazide, and glisolamide, have any significant effects on insulin binding to its receptor. In contrast the two biguanides tested, phenformin and metformin, increased insulin binding in all cell types by 44 to 101%. These studies raise the possibility, therefore, that biguanides may have a direct effect on insulin receptors and this effect may account for the known effects of biguanides to lower elevated blood sugar levels in diabetic patients.