Gemcitabine and pemetrexed are two novel antimetabolites with broad spectrum of antitumor activity and a safe toxicity profile. In addition, recent advances in cellular and molecular biology led to a better understanding of their mechanisms of action and resistance. Based on these latter advantages, several studies have been conducted using pemetrexed or gemcitabine either alone or with novel targeted therapies. Taken together, these recent data should result in a better and more specific use of these two very promising drugs.