Among the 114 children with retinoblastoma seen at St. Jude Children's Research Hospital 1962-1984, 11 have received treatment with chemotherapy for measurable extraocular disease which was present at diagnosis (seven patients) or developed later during the subsequent course of their disease (four patients). Metastatic disease involved the brain and spinal fluid of four persons, the orbit of five, the bone marrow of five, lymph nodes of four, and soft tissues of three individuals at the time of their treatments. Single agents or combinations were used. Two patients with orbital extension of primary retinoblastoma developed complete responses following chemotherapy and subsequently received orbital irradiation, and have had long-term disease-free survival. Additional responses developed in patients who received vincristine, cyclophosphamide, adriamycin, cisplatin, VM-26, and ifosfamide, singly or in combination. With future identification of effective chemotherapy, new studies may be focused upon patients with localized disease to reduce radiation dosage or the need for immediate surgical resection of all involved eyes.