Phosphorylation and dephosphorylation of cellular proteins by protein kinases and phosphatases represent important mechanisms for controlling major biological events. In the nervous system, protein phosphatases are contained in highly dynamic complexes localized within specialized subcellular compartments and they ensure timely dephosphorylation of multiple neuronal phosphoproteins. This modulates the responsiveness of individual synapses to neural activity and controls synaptic plasticity. These enzymes in turn play a key role in many forms of learning and memory, and their dysfunction contributes to cognitive deficits associated with aging and dementias or neurodegenerative diseases. Here, we review key modes of regulation of neuronal protein serine/threonine phosphatases and their contribution to disorders of learning and memory.