Hyperthermia may act additively or synergistically with a majority of clinically useful chemotherapeutic agents in vitro. In some cases enhanced responses are essentially linear at temperatures from 39 to 43 degrees C (thiotepa, the nitrosoureas, cisplatin), while other drugs become more effective only at 42 to 43 degrees (doxorubicin, bleomycin, amphotericin B). Synergism has been observed in vivo with methotrexate, cyclophosphamide, the nitrosoureas, doxorubicin, bleomycin, and cisplatin. Optimum enhancement occurs when heat and drug are given simultaneously. Clinical studies employing WBH at 41 to 41.8 degrees C have shown evidence of potential usefulness, but have been limited by high toxicity and a low benefit-to-risk ratio. Regional perfusion of metastatic melanoma of the extremity treated with L-phenylalanine mustard at 40 to 41 degrees C was significantly better than when treated with the drug alone, but some investigations suggest that heat alone may be just as effective. Localized hyperthermia combined with nearly all the standard types and doses of single and combination agents has shown objective responses in about one third of patients treated, without evidence of increased drug toxicity by either the IV or IA route. Responses appear to be thermal-dose related. Maximum enhancement appears at about 40 to 43 degrees C and prior drug resistance does not appear to confer heat resistance. The lack of enhanced drug toxicity with loco-regional hyperthermia with potential improvement in response of advanced disease suggests that thermochemotherapy is a viable and important option to drug treatment alone. Further in vitro, in vivo, and clinical studies are needed to increase our understanding of drug-heat interactions for the optimization of therapy.