<p>The neuroimmune system, an extensive bidirectional communication system between neural cells and immune cells, utilizes evolutionarily conserved molecules, including cytokines, chemokines and trophic factors that participate as mediators in both directions. While the initial discovery of classic immune molecules in the brain was interpreted as neuroinflammation, a broad literature demonstrates their essential roles in cognition during homeostatic brain function. These mechanisms include neural correlates of learning and memory, such as strengthening of neuronal networks and the generation of new neurons and synaptic connections. These processes take place throughout the brain, especially in the hippocampus, a major component of the brain of humans and other vertebrates that consolidates short-term memory into long-term memory and supports spatial navigation. This Review explores recent developments and understanding of immune molecules that orchestrate and participate in molecular mechanisms of memory formation. It also considers their potential efficacy as new targets to treat memory disorders.</p>