Hypoglycemic detection, long attributed exclusively to the brain, is now known to occur in the portal vein. Using the local irrigation technique, it has been repeatedly shown that hypoglycemia in the portohepatic region is essential to engendering the full catecholamine response. This same approach was recently used to constrain the locus for hypoglycemic detection to the portal vein, not the liver. The quantitative contribution of the portal vein glucosensors toward hypoglycemic detection appears dependent on the rate of fall in blood glucose. Thus, when hypoglycemia develops slowly, detection occurs primarily, if not exclusively, in the portal vein. Portal glucose sensing has now been demonstrated in several species-most importantly in humans. Although the mechanism of portal glucose sensing remains to be fully elucidated, it does appear to involve afferent innervation. Understanding glycemic detection has taken on added importance, as hypoglycemia has emerged as the primary limitation toward effective modern diabetes treatment.