Non-small-cell lung cancer (NSCLC) accounts for 80% of all lung cancer, which is the leading cause of cancer mortality. The majority of NSCLC patients present with advanced disease at diagnosis. Standard chemotherapy using platinum-containing doublets has reached a therapeutic plateau with a median survival of ~1 year. The development of more effective strategies in the first-line setting remains challenging. In selected chemotherapy-naïve, advanced, non-squamous patients, the combination of bevacizumab with chemotherapy was shown to produce better outcomes than chemotherapy alone. The potential benefit of maintenance/sequential treatment after initial platinum-based chemotherapy should be discussed in detail with each patient. Epidermal growth factor receptor (EGFR) mutation determination should be carried out in subgroups of patients characterized by a high prevalence of sensitizing mutations. When a mutation is present, first-line treatment with an EGFR tyrosine kinase inhibitor may be considered. Finally, a phase I study using an oral ALK inhibitor has produced promising results in NSCLC patients with ALK rearrangements, indicating that ALK represents a new therapeutic target in a molecularly defined subset of NSCLC. Ongoing studies in first-line therapy are focusing on targeted therapies and patient selection.