Better treatments are needed for high-grade gliomas (HGG), and new ways of treating this disease should be tested. The investigators want to see if giving medicine before radiation works well. After radiation, MRI scans can be harder to understand because radiation changes how the brain looks on the scan. If new medicines are given before radiation, the scans are easier to read.

First, the investigators need to find out if giving chemotherapy early works using a drug we already know can treat gliomas. The investigators will start with temozolomide, which is the only chemotherapy approved by the FDA for HGG. If this approach is successful, the investigators can then test new drugs using this screening method.

Inclusion Criteria:

1. Pathologic diagnosis of high-grade glioma

2. Residual measurable post-operative contrast enhancing tumor

3. Lack of urgency in requiring immediate radiation or chemotherapy (mass effect, mid-line shift, herniation, etc.)

4. Ability to provide informed consent

5. Willingness to comply with all study procedures and availability for the duration of the study

6. Male or female, aged 18-80.

7. Karnofsky Performance Status ³70%.

8. Patients must have the following organ and marrow functions:

   Absolute neutrophil count ≥1,500/µL Platelets ≥100,000/µL Hemoglobin ≥ 9 g/dL Total bilirubin £ 1.5 × institutional upper limit of normal (ULN), (except for patients with known Gilbert's syndrome who must have normal direct bilirubin) AST (SGOT)/ALT (SGPT) £ 2.5 × ULN Creatinine £ 1.5 × ULN OR Creatinine clearance ≥ 60 mL/min/1.73m2 APTT/PTT ≤ 1.5 × ULN Sodium ≥ the institutional lower limit of normal

9. Ability to take oral medication and be willing to adhere to the pre-radiation temozolomide regimen

10. For females of reproductive potential: use of highly effective contraception for at least 1 week prior to screening and agreement to use such a method during study participation and for an additional 4 weeks after the end of pr-radiation temozolomide administration

11. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner

12. Patients must have measurable disease as defined by RANO criteria.

Exclusion Criteria:

1. Patients receiving any other investigational agents are ineligible.
2. Patients who had Gliadel wafer or other local therapy placed in the tumor cavity during the tumor resection.
3. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to TMZ are ineligible.
4. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible.
5. Pregnant women are excluded from this study because TMZ has potential for teratogenic or abortifacients effects. Breastfeeding should be discontinued if the mother is treated with TMZ.