Multimodality therapy with combination chemotherapy employing etoposide, high-dose methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO), and adjuvant radiotherapy and surgery, when indicated, has resulted in cure rates of 80-90% in patients with high-risk metastatic gestational trophoblastic tumors. However, approximately 25-30% of high-risk patients will have an incomplete response to first-time chemotherapy or will relapse from remission. Most of these patients will have a clinicopathologic diagnosis of choriocarcinoma, metastases to sites other than the lung and vagina, more than eight metastases and/or failed inappropriate previous chemotherapy, resulting in very high World Health Organization scores. Salvage chemotherapy with cisplatin/etoposide, usually in conjunction with bleomycin or ifosfamide, as well as surgical resection of sites of resistant disease in selected patients, will result in a cure in most patients. New technology, such as the use of colony-stimulating factors to prevent treatment delays and dose reductions or high-dose chemotherapy with or without autologous bone marrow transplantation or peripheral blood stem cell support, may play an important role in the future management of patients who develop drug resistance.