The purpose of this study is to determine if the combination of 2 chemotherapy drugs called pemetrexed and gemcitabine might be effective treatment for head and neck squamous cell cancer. The researchers want to find out what effects, good and/or bad, that this treatment has on head and neck cancer.

Pemetrexed (500 mg/m2) and gemcitabine (1250 mg/m2) will be given together on Days 1 and 15 of a 28 day cycle in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Patients will not have received more than 2 prior chemotherapy regimens in the recurrent/metastatic disease setting. Vitamin B12 and folate supplementation will be administered per standard guidelines for pemetrexed chemotherapy.

The primary endpoint is the objective radiologic response rate. Radiologic imaging of evaluable disease will take place after every 2 cycles. Patients may remain on study until progression of disease or unacceptable toxicity.

Inclusion Criteria:

• Patients must have microscopically confirmed epidermoid/squamous cell carcinoma (HNSCC) of the oral cavity, pharynx, larynx, paranasal sinus, or head/neck squamous cell carcinoma unknown primary.
• Patients must have recurrent or metastatic disease which is not amenable to curative-intent therapy with surgery or radiation.
• No more than 2 prior cytotoxic therapies in the recurrent or metastatic disease setting are permitted.
• Patients must be at least 18 years of age.
• Karnofsky Performance status must be ≥ 70%.
• Disease must be measurable by RECIST criteria.
• At least 4 weeks must have elapsed from previous radiation therapy. Patient must have recovered from the acute toxic effects of treatment prior to study enrollment.
• Prior radiation therapy to ≤ 25% of bone marrow is allowed. Prior radiation to the whole pelvis and/or brain is not allowed.
• Adequate organ function
• Patients of childbearing potential must have a negative test for pregnancy at time of enrollment based on a urine or serum pregnancy test. Patients must agree to use a reliable method of birth control during and for 3 months following the last dose of study drug.
• Patient must reside in geographic proximity to MSKCC for adequate follow-up during treatment, per investigator discretion.
• Patients must sign an informed consent document.

Exclusion Criteria:

• Previous exposure to pemetrexed (Alimta) or gemcitabine (Gemzar).
• Pregnancy or breast-feeding.
• Serious concomitant systemic disorders (for example, active infection) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient's ability to complete the study.
• History of any brain metastases.
• Inability or unwillingness to take folic acid, vitamin B12 supplementation, or dexamethasone.
• Patients will be excluded if they will be unable to hold use of nonsteroidal antiinflammatory agents (NSAIDS) with short elimination half lives