Owing to the slow but sustained progress made in lung cancer treatment over the last 20 years, several therapeutic options are now available in the first-line setting as well as for patients who have progressed after one or more previous lines of treatment. Considering the growing array of choices currently confronting clinicians involved in the treatment of advanced non-small cell lung cancer (NSCLC), an effort should be made to define the optimal treatment option in each disease setting and to identify a logical therapeutic strategy after initial disease progression. This is especially crucial in the management of young, fit patients, who may be suitable candidates for two or more lines of therapy. At present, a rational treatment strategy for advanced NSCLC may be designed on the basis of patient clinicopathological features and rely on evidence from large, well-conducted clinical trials. In a near future the results of prospective validation studies will provide more sophisticated approaches for the classification of lung cancer patients, allowing clinicians to make individualised treatment decisions based on tumour molecular profile and on novel, more refined predictive/prognostic factors.