Patients with primary malignant brain tumors have a poor prognosis. Standard treatment includes surgical resection, radiation therapy and chemotherapy. Topoisomerase I inhibitors such as topotecan and irinotecan (CPT-11) represent one class of chemotherapy drugs that have been used in this disease. Recent clinical trials have shown major antitumor activity in recurrent glioblastoma when adding the antiangiogenesis drug bevacizumab with CPT-11. The combination of targeted agents to topoisomerase I inhibitors represent a novel and promising approach. This review will summarize clinical trials with topoisomerase I inhibitors and discuss new treatment strategies for primary malignant brain tumors.