Glucokinase (GK) plays a key role as a glucose sensor in pancreatic β-cells and in the regulation of glucose utilisation in hepatocytes. Defects in the GK gene have been linked to maturity-onset diabetes of the young (non-insulin-dependent [MODY-2]), permanent neonatal diabetes (PNDM) and persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI). Expression of GK is regu-lated by the upstream pancreatic promoter or the downstream hepatocyte promoter by a scenario involving several transcription factors and signalling pathways that are not yet understood in full. Thus, the development of spe-cific drugs that enhance either GK activity or GK expression could be useful for treatment of the diabetic syndromes. Due to a recent breakthrough leading to the identification of a novel class of small molecules termed glucokinase activators, the old enzyme became a new target in diabetes therapy. Expert Opin. Ther. Patents (2005) 15(6):705-713