 Erlotinib is registered in all patients affected with NSCLC in second and subsequent lines with a small benefit on Overall Survival. Recent evidence suggest that patients with EGFR mutations have a clear benefit when they are treated with EGFR tyrosine kinase inhibitors, while the role of these drugs in wild-type EGFR patients, that are representing the large majority about 85-90, is still unclear and no properly planned trials assessed before this issue. Recently, indirect evidence on subgroup analyses on randomized trial suggest that chemotherapy might be superior to erlotinib in wild-type EGFR patients. 