Background: The insulinotropic effect of whey protein is not fully understood and has clinical implications in the regulation of chronic and acute hyperglycemia. Summary: This review describes the composition of whey protein and potential mechanisms through which whey exerts an insulinotropic effect, including increasing the gastric emptying rate, effect on incretin hormones particularly gastric inhibitory peptide and glucagon-like polypeptide-1, and whey's role as a dipeptidyl peptidase IV inhibitor. Recent clinical evidence on the use of whey protein concentrate, isolate and hydrolysate in the management of type 2 diabetes and in the acute care adult population is reviewed. Key Messages: The mechanism through which whey protein exerts its insulinotropic effect is multifactorial. Increasing evidence supports the potential use of whey protein in medical/nutritional therapy to manage glycemia; however, additional research is needed to determine the most appropriate dose, form and delivery method for whey supplementation.