Gemcitabine, a pyrimidine nucleoside antimetabolite, is one of the most promising new cytotoxic agents. The drug has shown activity in a variety of solid tumors, but appears to be most active in the treatment of non-small cell lung cancer. In this disease, several Italian investigators have evaluated gemcitabine in phase II and III clinical trials. Due to preclinical synergism with cisplatin, the Italian Lung Cancer Project played an important role to assess the efficacy and activity of the gemcitabine–cisplatin combination along with the best doses and schedule to adopt, thus leading to gemcitabine approval for first line treatment of advanced non-small cell lung cancer. Several Italian studies have also investigated gemcitabine non-platinum based combinations, gemcitabine in third generation platinum-based triplets and gemcitabine as second line therapy, but all these studies led to conflicting and inconclusive results. The low toxicity profile makes the drug a valid option for unfit and elderly patients. The Multicenter Italian Lung Cancer in the Elderly Study was a phase III randomized trial conducted in elderly patients with advanced non-small cell lung cancer that showed that single agent gemcitabine is at least as effective as either single agent vinorelbine or the combination of gemcitabine and vinorelbine. In the neoadjuvant treatment of stage III disease, a number of phase II studies with third generation platinum-based doublets or triplets have been conducted by Italian investigators with encouraging results. Current clinical trials are addressing the role of gemcitabine in combination with new targeted therapies. Future studies should be designed in order to identify subgroups of patients who are more likely to benefit from gemcitabine chemotherapy.