Hyperthermia induces conformational changes of macromolecular structures. Such effects lead to a sudden inhibition of DNA, RNA and protein synthesis and a breakdown of membranes and of the cytoskeleton. These alterations can be very important for the mechanism of cell killing by hyperthermia. Furthermore hyperthermia induces a number of immediate metabolic changes by increasing metabolic rates. These alterations have been studied especially in intermediary metabolism like glycolysis, citrate cycle, lipid metabolism and oxidative phosphorylation. An increased turnover of ATP has been observed in cells and tissues during heating. These changes lead to a depletion of energy reservoirs. Also, disregulations occur at certain metabolic key points. Thus, the pathway of pyruvate into the citrate cycle via acetyl-CoA is apparently reduced in heated melanoma cells in vitro. The redox ratios of lactate/pyruvate, NADH/NAD+ and others are decreased. When the same melanoma cells are grown as a xenograft on nude mice the metabolic rates are also enhanced; however, the lactate/pyruvate ratio increases during a localized heating of the tumour. The extent of this effect is very variable in individual tumours and is apparently correlated with the blood flow. These alterations can be enhanced by glucose loading and can be used as an indicator of hypoxia within the tumour. Thus, the micromilieu can be modified by these metabolic effects in such a way that the thermosensitivity is increased. The data show that metabolic processes are directly and indirectly involved in cell killing by hyperthermia.