After first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC), many patients remain candidates for a second-line treatment. Docetaxel, pemetrexed and erlotinib are currently approved in the USA and Europe as second-line therapy for NSCLC, while gefitinib is approved and licensed in Europe, but not in the USA, for EGF receptor-mutated patients in the same setting. Results of the registration trials for these four agents show similar efficacy in terms of objective response rate and survival, but significantly different toxicity and tolerability. Therefore, at the time of failure of first-line treatment, it is crucial to evaluate different clinical factors that could help choose the second-line treatment of metastatic NSCLC, as performance status and comorbidities; new predictive biomarkers will be validated in future trials. Considering the different predictive and prognostic factors, tyrosine kinase inhibitors could be a valid option for second-line treatment of NSCLC.