Hyperthermia can cause brain damage and also exacerbate the brain damage produced by stroke and amphetamines. The developing brain is especially sensitive to hyperthermia. The severity of, and mechanisms underlying, hyperthermia-induced neuronal death depend on both temperature and duration of exposure. Severe hyperthermia can produce necrotic neuronal death. For a window of less severe heat stresses, cultured neurons exhibit a delayed death with apoptotic characteristics including cytochrome c release and caspase activation. Little is known about mechanisms of hyperthermia-induced damage upstream of these late apoptotic effects. This chapter considers several possible upstream mechanisms, drawing on both in vivo and in vitro studies of the nervous system and other tissues. Hyperthermia-induced damage in some non-neuronal cells includes endoplasmic reticular stress due to denaturing of nascent polypeptide chains, as well as nuclear and cytoskeletal damage. Evidence is presented that hyperthermia produces mitochondrial damage, including depolarization, in cultured mammalian neurons.