This article reviews evidence showing that neurochemical modulators can regulate the relative participation of the hippocampus and striatum in learning and memory tasks. For example, relative release of acetylcholine increases in the hippocampus and striatum reflects the relative engagement of these brain systems during learning of place and response tasks. Acetylcholine release is regulated in part by available brain glucose levels, which themselves are dynamically modified during learning. Recent findings suggest that glucose acts through astrocytes to deliver lactate to neurons. Brain glycogen is contained in astrocytes and provides a capacity to deliver energy substrates to neurons when needed, a need that can be generated by training on tasks that target hippocampal and striatal processing mechanisms. These results integrate an increase in blood glucose after epinephrine release from the adrenal medulla with provision of brain energy substrates, including lactate released from astrocytes. Together, the availability of peripheral and central energy substrates regulate the processing of learning and memory within and across multiple neural systems. Dysfunctions of the physiological steps that modulate memory—from hormones to neurotransmitters to metabolic substrates—may contribute importantly to some of the cognitive impairments seen during normal aging and during neurodegenerative diseases. © 2013 Wiley Periodicals, Inc.