Both pemetrexed and cetuximab have single agent activity in NSCLC and non-overlapping toxicity profiles. While 2-drug combination therapy has proven superior to single agent therapy in the first-line setting of NSCLC, no such phase III trials have been reported in the second-line setting. Therefore, the purpose of this study is to determine the feasibility of combining these drugs, assessing the toxicity profile, determining the MTD and evaluating the activity of the combination in an expanded phase II setting. If the combination appears to have promising activity, further evaluation of this regimen may be warranted comparing it to single agent pemetrexed or cetuximab alone.