Metallothioneins (MTs) are a family of proteins characterized by their high heavy metal (Zn²⁺, Cu⁺) content and an unusual cysteine abundance. MT-I and MT-II are two MT isoforms which are expressed in most tissues including the brain, whereas MT-III (also called Growth Inhibitory Factor, GIF) and MT-IV are expressed predominantly in the CNS and in keratinizing epithelia, respectively. All MT isoforms have been implicated in disparate physiological functions such as Zn²⁺ and Cu²⁺ metabolism, protection against oxidative agents, or adaptation to stress, whereas MT-III has been involved additionally in neuromodulatory events and in the pathogenesis of Alzheimer disease. To gain insight into how MTs are regulated in the brain is essential for elucidating the potential importance of these proteins for a normal brain physiology as well as in pathophysiological states. In this review we examine the biology of the MT family in the context of their expression and roles in the CNS.