N-methyl-D-aspartate receptor (NMDAR) activation is obligatory for the induction of diverse forms of synaptic plasticity. The molecular composition and the function of NMDARs are themselves modified by synaptic activity, which, in turn, alters the ability of synapses to undergo subsequent plastic modification. This homeostatic control of synaptic plasticity is well-known for the experience-dependent development of sensory cortices. However, it is now becoming clear that NMDAR properties may not only be altered at juvenile, but also at mature synapses. Diverse types of behavioral manipulation, such as sensory experience, learning and sleep deprivation alter the NR2A/NR2B ratio of hippocampal or cortical NMDARs. As an additional facet to the dynamics of NMDAR function, NMDAR trafficking is regulated by G-protein-coupled neurotransmitter receptors implicated in learning and arousal, such as orexin and dopamine. These findings suggest that mature glutamatergic synapses may be modified by recent activity via alterations in synaptic NMDAR function. Rapid forms of NMDAR trafficking, perhaps controlled by the neurochemical environment featuring specific states of arousal and learning, may regulate plasticity and modulate cognitive abilities in adulthood.