Hyperthermia is a recognized teratogen in animals and there is strong evidence that it also causes significant damage to human embryos. Studies with induced hyperthermia in pregnant animals defined the defects which are produced, the susceptible stages of development, and threshold doses of heat required to cause defects. The in vivo experiments lacked precision because of variability of embryonic development at a given conceptual age, varying maternal responses to agents causing temperature elevations, the difficulty in measuring embryonic temperature and the possibility that defects were caused by toxic changes in maternal metabolism. These variables were eliminated by the use of postimplantation whole rat and mouse embryo cultures, which were exposed to various doses of heat at closely defined stages of development. The studies showed that heat acts directly on embryos and that elevations of 2 degrees C and greater sustained over early rat organogenesis cause defects mainly by causing apoptotic cell death especially in the developing central nervous system. A moderate, non damaging exposure is followed within 15 min by protection for up to 8 h against a more severe and otherwise teratogenic exposure. The protective heat shock response is accompanied by a reduction of normal protein synthesis and concurrent synthesis of heat shock proteins (HSP90, 71, 47, 27). Most HSP in these families are also present constitutively in embryos, probably having important roles in protecting newly synthesized proteins from aggregation and facilitating folding into their normal functional configurations. The appearance of induced HSP and hsp mRNA at known sites of thermal damage suggests a protective role. Heat induced cell death by apoptosis is a feature of teratogenic damage to the developing brain. Apoptosis could be a by-product of a damaging heat exposure because of a priority favoring induction of the heat shock response over the normal gene program for organogenesis, survival being achieved at the expense of normal development.