The heat response in vitro and in vivo of five human melanoma xenografts grown in athymic nude mice was studied. The melanomas differed significantly in terms of heat sensitivity both in vitro and in vivo. At least two different mechanisms governed the overall heat response of the melanomas in vivo: the primary cell death, induced during treatment, was due to direct cytotoxic effects of the heat; the secondary cell death, induced after completion of treatment, was due to heat-induced vascular damage. The activation energies for the melanomas were not significantly different in vitro and in vivo at temperatures above the inflection point of the Arrhenius curves. Below the inflection point, on the other hand, the activation energies were higher in vitro than in vivo, probably as a consequence of differences in the physiological conditions in vitro and in vivo. The heat responsiveness of the melanomas in vivo was not related to the radioresponsiveness, whether the heat treatment was given at a low or a high temperature. All melanomas developed thermotolerance after a priming heat treatment. The thermotolerance differed significantly in magnitude among the five melanomas. It was concluded from the thermotolerance data that clinical treatment protocols probably should not prescribe more than one hyperthermic treatment per week.