A subset of glutamatergic synapses in the central nervous system contains zinc; it is sequestered into the lumen of synaptic vesicles, where it colocalizes with glutamate. Extracellularly applied zinc is known to interact with various postsynaptic receptors and channels; however, the role of endogenous vesicular zinc is still an enigma. The aim of this review is to present the physiology of tonic and phasic zinc modulation of excitatory and inhibitory signals and to discuss the potential role of zinc in synaptic plasticity. Zinc homeostasis is known to be altered under pathological conditions. The importance of the careful investigation of the potential sources of zinc involved in physiological and pathological processes is highlighted.