During the last 10 years, gene therapy for brain tumors has known peaks and valleys. The first attempts to induce therapeutic effect, using retrovirus to transduce the HSV-TK gene and adenovirus to transfer wild-type p53 cDNA, failed significantly to improve the survival of the patients. In both cases, the failure was attributed to vector deficiencies, also termed the ‘vector gap’. To address the problem of delivery, investigators have moved from replication-deficient vectors to replication-competent, tumor-selective viruses. These viruses are currently being tested in the clinical setting. In this review, we discuss the progress made with herpes simplex viruses (G207), reoviruses that naturally target Ras pathways, adenoviruses targeted to the p53 pathway (ONYX-015), and third-generation adenovirus targeted to the Rb pathway (Delta-24-RGD). Because cancer frequently requires multiple therapies for curative effect, we also comment on the combination of oncolytic viruses with conventional therapies. Specifically, we mention the combined used of oncolytic viruses and chemotherapy as well as the potential manipulation of the DNA repair machinery to enhance virus replication, virus potency, and antiglioma effect. In the future, oncolytic viruses will be administered to patients in combination with other biological agents such as antibodies and cancer vaccines.