Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all cases of lung cancer, and it is the most common cause of death in men and second only to breast cancer in women. Combination chemotherapy, usually platinum-based, is currently the first-line therapy of choice, however, the prognosis for patients with advanced NSCLC remains poor with a median survival time of 8-11 months and a 1-year survival rate of 30%. The treatment of NSCLC is therefore a major unmet need and new therapies focusing on the molecular mechanisms that mediate growth of NSCLC cells are urgently needed. The availability of agents targeted against the EGF-R, as well as the anti-VEGF agent bevacizumab, have provided some clinical benefit. Numerous other novel targeted therapies are now in clinical development and may have potential for overcoming the limitations associated with currently available drugs. In addition, a few new agents targeting novel pathways are also under clinical evaluation. The search for innovative therapeutic agents in NSCLC that are more effective and have fewer side effects than older chemotherapeutic drugs has spurred the development of more than 500 molecularly targeted agents and thereby has introduced the concept of individualized therapy. In this article we review clinical data for molecular-targeted therapies in NSCLC, with emphasis on EGF-R, VEGF-R and other novel targets. Nonetheless, for most patients with NSCLC targeted therapies have not dramatically changed clinical outcome, and resistance has emerged as a clinical problem. The molecular complexity of lung cancer underlies these disappointments and stresses the need for optimizing treatment by seeking a more personalized approach to care. Therefore, clinical trials that investigate the activity of novel agents, and incorporate patient selection based on clinical and molecular factors, are required. The increased sophistication of preclinical models and the enrollment of patients in clinical trials that include measurements of biomarkers will clearly help to identify patients who are likely to benefit from therapy, as well as further define mechanisms of resistance to therapy.