Metallothioneins (MTs) constitute a family of cysteine-rich metalloproteins involved in cytoprotection during pathology. In mammals there are four isoforms (MT-I − IV), of which MT-I and -II (MT-I + II) are the best characterized MT proteins in the brain. Accumulating studies have demonstrated MT-I + II as multipurpose factors important for host defense responses, immunoregulation, cell survival and brain repair. This review will focus on expression and roles of MT-I + II in the disordered brain. Initially, studies of genetically modified mice with MT-I + II deficiency or endogenous MT-I overexpression demonstrated the importance of MT-I + II for coping with brain pathology. In addition, exogenous MT-I or MT-II injected intraperitoneally is able to promote similar effects as those of endogenous MT-I + II, which indicates that MT-I + II have both extra- and intracellular actions. In injured brain, MT-I + II inhibit macrophages, T lymphocytes and their formation of interleukins, tumor necrosis factor-α, matrix metalloproteinases, and reactive oxygen species. In addition, MT-I + II enhance cell cycle progression, mitosis and cell survival, while neuronal apoptosis is inhibited. The precise mechanisms downstream of MT-I + II have not been fully established, but convincing data show that MT-I + II are essential for coping with neuropathology and for brain recovery. As MT-I and/or MT-II compounds are well tolerated, they may provide a potential therapy for a range of brain disorders.