The prognosis of patients with metastatic melanoma remains poor. In patients with distant metastases only low response rates between 10% and 15% have been achieved by the most effective cytostatics in single-agent therapy leading to a mean 5-year survival rate of less than 5%. More aggressive treatment regimens using multidrug chemotherapy yielded response rates of up to 40% but failed to show a significant benefit in overall survival compared to single-agent therapy. However, complete remissions of metastatic lesions after multidrug cytostatic regimens have been reported in some cases of melanoma patients. To evaluate an in vitro test system providing information on the drug sensitivity profile of melanoma cells, we examined tumor tissue specimens from 31 metastatic melanoma patients with an ATP-based chemosensitivity assay (ATP-TCA) testing eight anticancer drugs alone or in different combinations. Chemosensitivity was assessed using a luciferin-luciferase- based luminescence assay providing individual chemosensitivity indices for each test drug. We found a heterogeneous chemosensitivity in the melanoma tissue samples tested. The highest sensitivity was detected for the combination of treosulfan and gemcitabine, with 76% of the tissue samples revealing high sensitivity and 10% resistance, followed by the combination of paclitaxel and doxorubicine (66%/0%), gemcitabine and cisplatin (55%/21%),and paclitaxel and cisplatin (46%/8%). Our data indicate that the ATP-TCA can be used to select patients who might benefit from an individually adapted cytostatic therapy. On the basis of these results a multicenter trial has recently been initiated to evaluate the feasibility and predictive value of an ATP-TCA directed chemotherapy in metastatic melanoma patients.