First-line treatment of malignant gliomas invariably includes surgery when feasible, and often adjuvant radiotherapy with or without chemotherapy; at progression or recurrence, the only remaining possibility is chemotherapy. While the role of first-line treatment has been established by many randomized studies, second-line treatment is not as well defined. To analyze the difficulties encountered with cytotoxic drugs in relation to both the blood-brain barrier and drug resistance, we examined the results obtained by single-agent chemotherapy, drug combinations, and biological response modifiers. Our findings confirmed that the nitrosoureas are the most active substances at the time of recurrence; these agents give an approximately 30% global response rate, with about 20 weeks' survival. Although no comparative randomized studies regarding single- versus multiple-agent chemotherapy are available, the latter approach, including nitrosourea, can obtain an up to 40% rate of response, with survival ranging from 30 to 50 weeks. The role of interferons has been very controversial; individually, alpha- and beta-interferons seem to give a 20% response rate, with 20 weeks' survival. To date, they have never been used in combination with cytotoxic drugs, but they may prove synergistic without increasing toxicity. Studies addressing the quality of life of these patients are not available, and it is clear that we need more basic research in this field.