Two peripheral signaling routes have been proposed to account for the ability of peripheral substances such as glucose to modulate memory processing in the brain. One possible signaling route is by crossing the blood-brain barrier to act directly on brain. A second route involves activation of peripheral nerves with resulting changes in neural activity carried by peripheral nerves to the brain. Because the vagus nerve is a major neural pathway between the periphery and brain, peripherally acting modulators of memory modulators may act via vagal afferents to the brain to enhance memory processing. In the present experiments, systemic injections of either D-glucose or L-glucose, a metabolically inactive enantiomer, facilitated performance of rats on a four-arm alternation task, but at very different doses (D-glucose, 250 mg/kg; L-glucose, 3,000 mg/kg). The enhanced performance seen with L-glucose, but not that seen with D-glucose, was attenuated by vagotomy. These findings suggest that the mechanisms by which these enantiomers act to enhance memory are quite different, with L-glucose acting via vagal afferents but D-glucose acting by other means, including direct modulation of central nervous system (CNS) processes by D-glucose.