The enzyme glucokinase (GK) regulates the rate of glucose metabolism in many tissues, including liver, the pancreatic b cells, certain neurons, enteroendocrine cells, and the pituitary, serving as a glucose sensor in many of these. Thus, GK plays a critical role in glucose homeostasis. Spontaneous mutants of GK in humans result in autosomal-dominant hypo- and hyperglycemia syndromes described as "GK disease." GK activator drugs have been discovered that lower blood glucose in normal and diabetic animals and promise to be useful in the treatment of type 2 diabetes mellitus. There is no question that the GK molecule and related issues will continue to be a fruitful topic for future research.