Brain zinc homeostasis is strictly controlled under healthy conditions, indicating the importance of zinc for physiological function in the brain. A part of zinc in the brain exists in the synaptic vesicles, is released from a subclass of glutamatergic neurons (i.e., zincergic neurons), and serves as a signal factor (Zn2+ signal) in the intracellular (cytosol) compartment as well as in the extracellular compartment. Zn2+ signaling is dynamically linked to glutamate signaling and may be involved in synaptic plasticity, such as long-term potentiaion and cognitive activity. In zincergic synapses, intracellular Zn2+ signaling in the postsynaptic neurons, which is linked to Zn2+ release from zincergic neuron terminals, plays a role in cognitive activity. When nonzincergic synapses participate in cognition, on the other hand, it is possible that intracellular Zn2+ signaling, which is due mainly to Zn2+ release from the internal stores and/or metallothioneins, also is involved in cognitive activity, because zinc-dependent system such as zinc-binding proteins is usually required for cognitive process. Intracellular Zn2+ dynamics may be modified via an endocrine system activity, glucocorticoid secretion in both zincergic and nonzincergic neurons, which is linked to a long-lasting change in synaptic efficacy. On the basis of the evidence of cognitive decline caused by the lack and/or the blockade of synaptic Zn2+ signaling, this article summarizes the involvement of intracellular Zn2+ signaling in zincergic synapses in cognition and a hypothetical involvement of that in nonzincergic synapses. © 2014 Wiley Periodicals, Inc.