The involvement of the hippocampus and the prefrontal cortex in cognitive processes and particularly in learning and memory has been known for a long time. However, the specific role of the projection which connects these two structures has remained elusive. The existence of a direct monosynaptic pathway from the ventral CA1 region of the hippocampus and subiculum to specific areas of the prefrontal cortex provides a useful model for conceptualizing the functional operations of hippocampal-prefrontal cortex communication in learning and memory. It is known now that hippocampal to prefrontal cortex synapses are modifiable synapses and can express different forms of plasticity, including long-term potentiation, long-term depression, and depotentiation. Here we review these findings and focus on recent studies that start to relate synaptic plasticity in the hippocampo-prefrontal cortex pathway to two specific aspects of learning and memory, i.e., the consolidation of information and working memory. The available evidence suggests that functional interactions between the hippocampus and prefrontal cortex in cognition and memory are more complex than previously anticipated, with the possibility for bidirectional regulation of synaptic strength as a function of the specific demands of tasks.