Hyperthermia combined with chemotherapy is a complicated and poorly understood area, but one that portends great biological and clinical interest. The interrelationship of heat to vascular supply of tumor and normal organs that metabolize chemotherapy agents is complicated. The evocation of thermotolerance by chemical agents is a largely unexplored area. A class of chemotherapy agents that increase in cytotoxicity linearly with increasing temperature are the alkylating agents cisplatinum, mitomycin C, and mitoxantrone. A class of chemotherapy agents that increase in cytotoxicity only after a threshold temperature above 42 degrees are Adriamycin, bleomycin, and actinomycin D. Time sequencing of heat and Adriamycin affects cytotoxicity, implying a membrane effect of the heat and drug interaction. A new class of drugs thought not to be chemotherapy drugs because they are not cytotoxic at 37 degrees but are cytotoxic at greater than 41.5 degrees provides a new area of research. Chemotherapy agents that do not change in cytotoxicity with heat include the Vinca alkaloids, amsacrine, and 5-fluorouracil. In order to examine the complex interaction of heat and chemotherapy agents, whole animal models of tumor and normal tissue effects are extremely important.