Inclusion Criteria:

1. Non-small cell lung cancer patients Stage I-IV with surgically unresectable or medically inoperable tumors.
2. Patients for whom radiation therapy alone is the recommended treatment, who are not candidates for other chemo-radiation protocols.
3. For Phase I: Patients with any stage for whom palliative radiation therapy to 45 Gy/15 Fx is the recommended treatment (patients with obstructive pneumonia are eligible).
4. The primary tumor and/or regional lymphatic metastases must be evaluable radiographically.
5. Have at least one lesion greater than 2 cm in diameter measurable by CT.
6. Age at least 18 years old.
7. Karnofsky performance status >/=50, weight loss < 30% within the previous 6 months.
8. No prior invasive malignancies less than or equal to 3 years prior to study entry and no prior radiation to the thorax.
9. ALT or AST < 2.5 ULN or alk phos (ALP) < 2.5 x ULN, or < 5x ULN if judged by the investigator to be related to liver metastases
10. Total bilirubin < 1.5 x ULN or <3 x ULN if related to liver metastases
11. Serum creatinine < 1.5 x ULRR or creatinine clearance greater than or equal to 50 mL/minute (calculated by Cockcroft-Gault formula.)
12. WBC > 3000/mm3, serum hemoglobin >/= 8 gm/dl, platelet count >/= 100,000/mm3, absolute granulocyte count >/= 2,000.
13. INR within normal laboratory value range and PT and PTT within 3 seconds of normal range.
14. Potassium must be within normal laboratory value range. Serum calcium and magnesium must be within normal range. Supplementation may be used to normalize.
15. Patients with distant metastases and life expectancy greater than or equal to 3 months are eligible.
16. Due to the experimental nature of ZD6474, female patients must be one year post-menopausal, surgically sterile, or using an acceptable method of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device or tubal ligation.) Male patients must be surgically sterile or using an acceptable method of contraception during their participation in this study.
17. A negative pregnancy test within 72 hours prior to administration of ZD6474 will be required for women of childbearing potential.
18. Patients must sign an informed consent indicating that they are aware of the investigational nature of the study in keeping with the policy of M.D. Anderson Cancer Center. Patients must also agree to study restrictions and return for required assessments. The only approved consent form is attached to this protocol.
19. Eligibility for Phase II: (A) Patients with medically inoperable stage I and II NSCLC for whom definitive XRT alone is recommended (not candidate for combined chemo-XRT), or, (B) Patients who received previous induction chemotherapy off protocol, not candidates for other chemo-XRT protocols, or, (C) Patients with stage III NSCLC for whom definitive XRT alone is recommended, or, (D) Patients with any stage for whom palliative radiation therapy to 45 Gy/15 Fx is recommended.
20. Patients who are blood donors should not donate blood during the trial and for 3 months following their last dose of trial treatment.

Exclusion Criteria:

1. Pregnancy or breast feeding
2. Bronchoalveolar carcinoma
3. Oxygen saturation less than 90% on room air or requirement for oxygen supplementation
4. Any condition that is likely to interfere with regular follow-up
5. Patient cannot have participated in any clinical trial involving conventional or investigational drugs within 4 weeks prior to administration of ZD6474
6. Patient cannot have received radiation therapy or chemotherapy within 4 weeks prior to administration of ZD6474 (6 weeks for nitrosoureas and mitomycin)
7. Patient cannot be receiving herbal remedies or other over-the-counter biologics (e.g., shark cartilage)
8. Patient cannot be receiving drugs with known significant 3A4 inhibitory effects (e.g., ketoconazole, erythromycin, and verapamil - See Appendix K)
9. Patient cannot be receiving drugs with known corneal toxicology (e.g., tamoxifen, chlorpromazine, amiodarone, and chloroquine)
10. Patients cannot have received previous treatment with agents that block the EGF or VEGF pathways
11. Patient cannot have serum calcium levels below the lower limits of normal.
12. Clinically significant cardiac event such as myocardial infarction; New York Heart Association (NYHA) classification of heart disease >/=2 (see Appendix J) within 3 months before entry; or presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia.
13. History of arrhythmia (multifocal premature ventricular contractions (PVCs), bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded.
14. QTc with Bazett's correction that is unmeasurable, or >/= 480 msec on screening ECG. If a patient has QTc >/= 480 msec on screening EKG, the screening EKG may be repeated twice (at least 24 hours apart). The average QTc from the three screening EKGs must be <480 msec in order for the patient to be eligible for the study.
15. Patients cannot have a history of QT prolongation with other medication
16. Patients cannot have a congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age.
17. Any concomitant medications that affect QTc or induce Torsades de Pointes (Appendix E) and cannot be discontinued
18. Left ventricular ejection fraction less than 45% measured by multigated blood-pool imaging (MUGA) or Echocardiogram for subjects with previous anthracycline therapy (total dose greater than 450 mg/m2) or significant cardiovascular disease
19. Patients cannot have a severe hypersensitivity reaction to drugs formulated with polysorbate 80
20. Patients cannot have any evidence of severe or uncontrolled systemic disease, including known Hepatitis B or HIV infection. Screening for chronic conditions is not required, although subjects known to have such conditions should not be enrolled.
21. Patient cannot have had any active cancer in addition to their current lung cancer within the last 3 years with the exception of superficial skin cancer (e.g., basal cell or squamous cell carcinoma)
22. Patient cannot have any CNS metastases, unless treated at least 4 weeks before entry, and stable without steroid treatment for 1 week
23. Patient cannot have any additional uncontrolled serious medical or psychiatric illness
24. Patients with other contraindication for radiation therapy as decided by the physician
25. Patients cannot have presence of a left bundle branch block (LBBB).
26. Hypertension not controlled by medical therapy (systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg)
27. Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy