Long-term potentiation (LTP) is the predominant experimental model for the synaptic plasticity mechanisms thought to underlie learning and memory. This review is focused on the contributions of genetics to the understanding of the role of LTP in learning and memory. These studies have used a combination of genetics, molecular biology, neurophysiology, and psychology to demonstrate that molecular mechanisms of synaptic plasticity are critical for learning and memory. Because of the large scope of this literature, we focus primarily on genetic studies of hippocampal-dependent learning. Altogether, these findings not only demonstrate a role for plasticity in learning, they also lay down the foundations for the new field of molecular and cellular cognition.