Phase II: The primary objective of the Phase 2 portion of this study is to determine the tumor response rates to ALIMTA plus oxaliplatin and oxaliplatin plus 5-fluorouracil and leucovorin in patients with locally advanced unresectable or Stage IV colorectal cancer that have not received prior chemotherapy for advanced disease. Patients will be randomly assigned to receive either ALIMTA plus oxaliplatin (Arm A) or Oxaliplatin plus 5-Fluorouracil and Leucovorin (Arm B). The Phase II component of the study will be activated for enrollment of patients via the Mayo Clinic Cancer Research Consortium mechanism. A comparison will be made of the side effects between regimens.