Chemotherapy (platinum-based doublet) remains a key component of treatment for early, locally advanced and metastatic non-small-cell lung cancer. In the last decade, several important studies, including randomized clinical trials involving the use of new chemotherapeutic agents or targeted therapies, have been published. Targeted therapies have been tried as an alternative to, in conjunction with or following failure of standard chemotherapy regimens. Biomarkers have also been identified that predict responsiveness to and outcomes with commonly used chemotherapeutic agents, as well as targeted therapies. A trend for individualizing therapy for each patient based on baseline demographic characteristics, especially tumor histology and expression of predictive biomarkers, has been witnessed in the recent past. In this article, we have summarized the available literature on the role of histology and molecular markers of clinical relevance in the treatment of non-small-cell lung cancer.