Metallothionein (MT) has been considered to play important roles in metal homeostasis and also in protecting against metal toxicities. There are four MT isoforms in mammalian cells. Recent studies using MT-I and -II genes knockout mice demonstrated that MT-I and -II are mainly involved in the protection against metal toxicities, oxidative stresses, and apoptosis. The expression of MT-II gene by zinc is regulated through activation of the zinc regulatory factor (ZRF). MT-III, a brain-specific isoform, plays a role in preventing neuronal sprouting and in the repair after brain damage.