Significant progress has been made toward understanding the mechanisms by which organisms learn from experiences and how those experiences are translated into memories. Advances in molecular, electrophysiological and genetic technologies have permitted great strides in identifying biochemical and structural changes that occur at synapses during processes that are thought to underlie learning and memory. Cellular events that generate the second messenger cyclic AMP (cAMP) and activate protein kinase A (PKA) have been linked to synaptic plasticity and long-term memory. In this review we will focus on the role of PKA in synaptic plasticity and discuss how the compartmentalization of PKA through its association with A-Kinase Anchoring Proteins (AKAPs) affect PKA function in this process.