The only approved agents for second-line therapy in unselected non-small-cell lung cancer are docetaxel and pemetrexed (chemotherapies) and erlotinib (targeted therapies). Several new molecular drugs have now entered clinical trials and are being compared with approved agents (e.g., vandetanib). Alternative pathways are also being explored to overcome resistance to established agents (c-MET and ALK inhibitors), and predictive factors are now crucial for the selection of drug and of patients (e.g., EGFR mutations). Better patient selection permits second-line treatment to be tailored according to disease identity, which confers a particular benefit in certain subgroups of patients. In this review, the authors examine existing trials comparing targeted therapies with the standard of care as second-line therapy for advanced non-small-cell lung cancer.