Inclusion Criteria:

1. Histologically or cytologically confirmed Stage IIIB/ IV NSCLC.
2. Relapsed after treatment with 1 or 2 prior chemotherapy regimens, at least 1 of which must have been a platinum-based treatment. Patients may have received pemetrexed as 1 of the prior therapies. Patients may not have received investigational therapy as their only prior therapy.
3. Recovered from the toxic effects of prior therapy.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. Smoked ≥ 100 cigarettes in their lifetime, whether a former or current cigarette smoker.
6. ≥ 18 years of age.
7. Adequate hematologic, hepatic, and renal function as defined by: white blood cell (WBC) count ≥ 2500 cells/μL (≥ 2.5 x 109 cells/L); absolute neutrophil count (ANC) ≥ 1500 cells/μL (≥ 1.5 x 109 cells/L); platelet count ≥ 100,000/μL; calculated creatinine clearance of ≥ 50 mL/min; total bilirubin ≤ 1.5 x the upper limit of normal (ULN); and aspartate aminotransferase (AST, serum glutamicoxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT, serum glutamic-pyruvic transaminase [SGPT]) ≤ 3 x ULN (if clearly attributable to liver metastases, ≤ 5 x ULN is permitted).
8. The patient has been on a regimen of 1-1.25 mg PO QD of folic acid for at least 7 days prior to randomization and has received 1 mg IM of vitamin B12 within 10 weeks prior to randomization.
9. Women of childbearing potential must be practicing a medically acceptable contraceptive regimen and must have a negative serum pregnancy test within 14 days prior to randomization. Patients who are postmenopausal for at least 1 year (> 12 months since last menses) or are surgically sterilized do not require this test.
10. Men who are not surgically sterile must be practicing a medically safe and effective contraceptive regimen from the time of study randomization, and agree to continue practicing until at least 90 days after the last administration of study treatment.
11. Accessible for repeat dosing and follow-up.
12. Given written informed consent (IC).

Exclusion Criteria:

1. Active concurrent primary malignancy (except non-melanoma skin cancer or in situ carcinoma of the cervix).

   If there is a history of prior malignancy, the patient must be disease-free for ≥ 5 years.

2. Use of any investigational drugs, biologics, or devices within 4 weeks prior to randomization.
3. Previous exposure to pralatrexate or erlotinib.
4. Women who are pregnant or breastfeeding.
5. Congestive Heart Failure Class III/IV according to New York Heart Association (NYHA) Functional Classification.
6. Uncontrolled hypertension.
7. Known HIV-positive status.
8. Symptomatic central nervous system (CNS) metastases or lesions for which treatment is required.
9. Major surgery within 2 weeks of study randomization.
10. Receipt of any conventional systemic chemotherapy within 4 weeks (6 weeks for nitrosoureas, mitomycin C), or RT within 2 weeks, prior to randomization.
11. Active infection or any serious underlying medical condition, which would impair the ability of the patient to receive protocol treatment.
12. Dementia or significantly altered mental status that would prohibit the understanding and giving of informed consent or limit study compliance.