A family of facilitative glucose transporters (GLUTs) is involved in regulating tissue-specific glucose uptake and metabolism in the liver, skeletal muscle, and adipose tissue to ensure homeostatic control of blood glucose levels. Reduced glucose transport activity results in aberrant use of energy substrates and is associated with insulin resistance and type 2 diabetes. It is well established that GLUT2, the main regulator of hepatic hexose flux, and GLUT4, the workhorse in insulin- and contraction-stimulated glucose uptake in skeletal muscle, are critical contributors in the control of whole-body glycemia. However, the molecular mechanism how insulin controls glucose transport across membranes and its relation to impaired glycemic control in type 2 diabetes remains not sufficiently understood. An array of circulating metabolites and hormone-like molecules and potential supplementary glucose transporters play roles in fine-tuning glucose flux between the different organs in response to an altered energy demand.