Metastatic non-small cell lung cancer remains a disease with a high annual incidence and annual mortality worldwide, with limitations in first-line treatment past a fixed amount of platinum doublet chemotherapy for patients that do not harbor a targetable genetic abnormality such as an EGFR mutation or ALK gene rearrangement. Previous attempts to extend first-line treatment past 4-6 cycles of conventional cytotoxic chemotherapy have been disappointing, resulting in diminished quality of life and increased toxicity without improvement of progression-free or overall survival. Several advances in third-generation chemotherapy and targeted agents have generated a renewed interest in maintenance therapy, with several randomized phase III trials reporting a significant improvement in progression-free and overall survival with manageable toxicity profiles. The availability of new chemotherapy agents, tyrosine kinase inhibitors, and immunotherapy agents with a more tolerable or nonoverlapping toxicity profile have resulted in improvements in progression-free survival and median overall survival in maintenance settings with specific agents such as pemetrexed and erlotinib. Patients who are responding to first-line therapy, have not suffered a detrimental decrease in quality of life or performance status, and understand the risks and benefits of further immediate chemotherapy should be considered for maintenance treatment.