The supraoptic nuclei of the hypothalamus display a remarkable anatomical plasticity during lactation, parturition and chronic dehydration, conditions associated with massive neurohypophysial hormone secretion. This structural remodeling is characterized by a pronounced reduction of the astrocytic coverage of oxytocin neurons, resulting in an increase in the number and extent of directly juxtaposed neuronal surfaces. Although the exact role played by such an anatomical remodeling in the physiology of the hypothalamo–neurohypophysial system is still unknown, several findings obtained over the last decade indicate that synaptic and extrasynaptic transmissions are impacted by these structural changes. We review these data and try to extrapolate how such changes at the cellular level might affect the overall activity of the system. One repercussion of the retraction of glial processes is the accumulation of glutamate in the extracellular space. This build-up of glutamate causes an increased activation of pre-synaptic metabotropic glutamate receptors, which are negatively coupled to neurotransmitter release, and a switch in the mode of action of pre-synaptic kainate receptors that control GABA release. Finally, the range of action of substances released from astrocytes and acting on adjacent magnocellular neurons is also affected during the anatomical remodeling. It thus appears that the structural plasticity of the hypothalamic magnocellular nuclei strongly affects neuron–glial interactions and, as a consequence, induces significant changes in synaptic and extrasynaptic transmission.