Systemic chemotherapy with platinum-based regimens provides modest improvements in survival and quality of life for patients with advanced-stage nonsmall-cell lung cancer (NSCLC). Extended first-line chemotherapy with combination regimens for more than 4 to 6 cycles is not recommended because of cumulative toxicities and lack of proven advantage in survival with the increased duration of therapy. The early use of an anticancer agent as maintenance therapy after disease stabilization or maximal response with platinum-based regimens is, therefore, being recognized as a new treatment paradigm in NSCLC. Maintenance therapy can extend first-line treatment and provide an acceptable balance between efficacy and toxicity. The essential prerequisites for maintenance therapy include good tolerability, ability to administer extended cycles of therapy without cumulative toxicity, and an increase in the duration of progression-free survival. Pemetrexed has recently been shown to improve the median PFS in the maintenance setting. Molecularly targeted therapies with cytostatic properties and documented tolerability also have the potential to be effective as maintenance therapy to maintain tumor regression after an initial response to chemotherapy. Consequently, the role of erlotinib and other molecular targeted agents in this treatment setting is under active investigation in ongoing phase 3 trials. This could potentially establish a new standard on the clinical utility of molecular targeted agents as maintenance therapy for patients with advanced-stage NSCLC.