In this review, we will: (i) first provide an outline of the evidence that brain glucose sensing is important for glucose homeostasis, (ii) give an overview of brain glucose-sensing mechanisms including those using glucokinase, (iii) then describe the current data supporting a role for brain glucokinase in the central control of glucose homeostasis and (iv) discuss how these processes may become altered in diabetes and related metabolic disorders. This evidence concerns the gene GCK and metabolic disease.