Glucose-phosphorylating enzyme, glucokinase (GK) plays a major role in glucose homeostasis primarily through its regulatory actions in pancreatic β-cells and liver hepatocytes. Conversion of glucose to glucose-6-phosphate by GK promotes glycogen synthesis in liver hepatocytes, and insulin release in the pancreatic β-cells. Small molecules called glucokinase activators (GKAs) which bind to an allosteric activator site of the GK enzyme have indeed been discovered and developed, and thus hold great promise as new, effective and safe antidiabetic agents. GKAs enhance the catalytic activity of GK and promising clinical trials in humans demonstrated that they are highly useful in the treatment of type 2 diabetes mellitus. Most of the reported GKAs include amide derivatives like benzamides, acrylamides, carboxamides, acetamides and acrylamides. Examples include Piragliatin, AZD1656, AZD6370, R1440 GKA2, GKA 50, YH GKA, PSN 010, and LY2121260. Recent findings on GKAs including lead compounds and overview of current hypothesis on mechanism of GK activation along with summary of the recently published patents as well as the GKAs of natural origin are reported in the present review.