The role of zinc in the brain was a subject of intense interest, based particularly on the observation that a chelatable zinc pool is found at glutamatergic synaptic vesicles and is co-released during synaptic activity. Studies utilizing nutritional zinc deficiency or chelation linked brain zinc to cell death during ischemia and a role in development as well as learning and memory. Numerous studies in recent years led to identification of multiple zinc transporters among them the ZnT3 that is responsible for zinc accumulation in the vesicles. Generation of transgenic animals lacking specific zinc transporters together with the availability of zinc dyes led a dramatic progress in our insight on the role of brain zinc homeostasis. In this chapter we will discuss mechanisms by which zinc induces neuronal signaling or neuronal death, and how these may link zinc to learning and memory, seizure, ischemia and Alzheimer's disease (AD). Finally, we will focus on the emerging importance of zinc signaling in glia and glial-neuronal interaction.