Zn 2+ is a potently toxic cation involved in the neuronal injury observed in cerebral ischemia, epilepsy, and brain trauma. Toxic Zn 2+ accumulation may result from either trans-synaptic Zn 2+ movement and/or cation mobilization from intracellular sites. To gain entry to the cytosol, Zn 2+ can flux through glutamate receptor-associated channels, voltage-sensitive calcium channels, or Zn 2+ -sensitive membrane transporters, while metallothioneins and mitochondria provide sites of intracellular Zn 2+ release. Intracellular Zn 2+ homeostasis is sensitive to patho-physiological environmental changes, such as acidosis, inflammation and oxidative stress. The mechanisms by which Zn 2+ exerts its neurotoxicity include mitochondrial and extra-mitochondrial production of reactive oxygen species and disruption of metabolic enzymatic activity, ultimately leading to activation of apoptotic and/or necrotic processes. Beside acute neuronal injury, an exciting new area of investigation is offered by the role of Zn 2+ dysmetabolism in Alzheimer's disease as the cation acts as a potent trigger for Aβ aggregation and plaque formation. Finally, recent findings suggest that alteration of Zn 2+ homeostasis might also be a critical contributor to aging-related neurodegenerative processes. Thus, multiple evidence suggest that modulation of intracellular and extracellular Zn 2+ might be an important therapeutical target for the treatment of a vast array of neurological conditions ranging from stroke to Alzheimer's disease.