Pemetrexed is a multitargeted antifolate that inhibits at least three folate dependent enzymes involved in DNA synthesis. Gemcitabine is a broadly active pyrimidine nucleoside antimetabolite that is incorporated into DNA and causes chain termination. Both pemetrexed and gemcitabine, as single agents, have shown antitumor activity in a wide range of solid tumors, including non-small-cell lung cancer (NSCLC). Based on preclinical in vitro and in vivo synergism of the combination of pemetrexed and gemcitabine, the 2 drugs were studied in several phase I and II trials in patients with advanced NSCLC. The published studies found response rates between 13 to 31%, with overall survival times similar to established standard chemotherapy regimens. The grade 3 or 4 toxicities with this combination are mainly haematologic, dermatologic and transaminitis. In this paper, we review the pemetrexed-gemcitabine combination in the treatment of NSCLC patients with regards to the rationale, clinical activity as well as the future directions for this new 2-drug combination.