Inclusion Criteria:

1. Patients with histologically proven World Health Organizations (WHO) grade III and IV malignant gliomas will be eligible for the phase I portion of this study. For the Phase II part, patients with histologically proven supratentorial WHO grade IV malignant glioma (GBM and gliosarcoma) will be eligible
2. There must be unequivocal evidence for tumor recurrence or progression by MRI scan and the patient must have received radiation therapy previously.
3. Patients must be capable of understanding and voluntarily signing an informed consent form.
4. Age >/=18 years at the time of signing the informed consent form.
5. Karnofsky performance status of >/=60 at study entry
6. Able to adhere to the study visit schedule and other protocol requirements.
7. For the phase I portion of the study, patients may have any number of prior relapses provided all other eligibility criteria, particularly the functional status, are met. For the phase II portion of the study, no more than 2 prior relapses provided. Patients must have failed prior radiation therapy and must have an interval >/=6 weeks from the completion of radiation therapy to the study entry. Tumor regrowth after chemoradiation followed by adjuvant chemotherapy is considered one relapse.
8. The baseline on-study MRI should be performed within 14 days prior to registration and on a steroid dosage that has been stable or decreasing for at least 5 days. If the steroid dose is increased between the date of imaging and the initiation of therapy (or at that time), a new baseline MRI is required. The same type of scan, i.e., MRI, must be used throughout the period of protocol treatment for tumor measurement.
9. Patients must have recovered from the toxic effects of prior therapy: 4 weeks from any investigational agents, two weeks from vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and 1 week for non-cytotoxic agents, e.g., interferon, tamoxifen, cis-retinoic acid, etc. (radiosensitizer does not count).
10. ( 9. continued) Patients who receive irinotecan for non-therapeutic purposes unrelated to this study (such as presurgically for obtaining pharmacology data for the agent) will be eligible to enter the study provided they have recovered from the toxic effects of the agent if any. Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.
11. Laboratory test results within these ranges: 1) Absolute neutrophil count >/= 1.5 * 10^9/L. 2) Platelet count >/= 100 * 10^9/L. 3) Serum creatinine </= 1.5 mg/dL. 4) Total bilirubin </= 1.5 mg/dL. 5) AST (SGOT) and ALT (SGPT) </= 2 * ULN.
12. Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide.
13. (12. continued) FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
14. Disease free of prior malignancies for >/= 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in-situ" of the cervix or breast.
15. This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender.
16. There must be unequivocal evidence for tumor recurrence or progression by MRI scan (Phase II surgical, pre-operative)
17. Ability to obtain sufficient tumor specimen for the performance of the biomarker studies in the opinion of the treating physician and surgeon (Phase II surgical, pre-operative)
18. Meets all the inclusion/exclusion criteria for the phase II study except patients are not required to be on a stable dose of steroids prior to surgery.(Phase II surgical, pre-operative)
19. Patient must meet the pre-entry pregnancy testing and birth control requirement prior to the first pre-operative dose of lenalidomide (Phase II surgical, pre-operative)
20. The patient has consented to the surgical resection and correlative lab evaluations (phase II surgical, pre-operative)
21. Post-operative MRI scan performed no later than 96 hours and on a stable or reducing dose of steroids. (if treatment begins more than 14 days after the 96 hour scan, a new MRI scan including DCE MRI if there is residual tumor will be required to serve as the baseline MRI for efficacy analysis) (Phase II surgical, post-operative)
22. Must have recovered from the effects of surgery. (phase II surgical, post-operative)
23. Must have confirmation of recurrent tumor by pathology criteria.(phase II surgical, post-operative)
24. The patient has followed the on study requirements for birth control and pregnancy testing since the initial pre-operative dose of lenalidomide. (phase II surgical, post-operative)
25. The post operative complete blood count (CBC) and chemistry panel meet the entry criteria # 11.
26. The patient continues to meet all the inclusion/exclusion criteria of the study outlined above except inclusion criteria #8. (phase II surgical, post-operative)
27. Able to take warfarin or use low molecular weight heparin for the duration of study treatment

Exclusion Criteria:

1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from providing informed consent.
2. Pregnant or breast feeding females.
3. Any condition, including the presence of clinically significant laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. These would include a) Active infection(including persistent fever) b) Diseases or conditions that obscure toxicity or dangerously alter drug metabolism c) Serious intercurrent medical illness (e.g.symptomatic congestive heart failure).
4. Known hypersensitivity to thalidomide or lenalidomide.
5. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
6. Prior recurrence with irinotecan - (prior treatment with lenalidomide as single agent is permitted). Patients who have received irinotecan for non-therapeutic purposes (for eg., as part of a pharmacology study without therapeutic intent) will remain eligible for enrollment into the study. Patients who have received thalidomide or lenalidomide not in combination with irinotecan or other cytotoxic agents remain eligible for enrollment into the study.
7. Concurrent use of other anti-cancer agents or treatments.
8. No exclusion to this study will be based on race. Minorities will actively be recruited to participate. The malignant glioma patient population treated at MDACC over the past year is as follows: 1) American Indian or Alaskan Native - 0. 2) Asian or Pacific Islander - <2%. 3) Black, not of Hispanic Origin - 3%. 4) Hispanic - 6%. 5) White, not of Hispanic Origin - 88%. 6) Other or Unknown - 2%. Total-100%
9. Patients must not be on enzyme inducing anticonvulsants; if the treating physician elects to change the medication to a non-enzyme inducing agent, a 1-week wash out period will be required after stopping Enzyme-Inducing Anti-Epileptic Drugs (EIAED) prior to initiation of irinotecan.