Over the past 5 to 10 years, we have reached a treatment plateau using standard platinum-based doublets in an unselected population of patients with advanced non-small cell lung cancer (NSCLC). Recent studies have focused on improving patient outcomes with new chemotherapeutic or targeted agents, as well as on individualizing therapy on the basis of patient characteristics such as tumor histology and biomarker analysis. This article summarizes recent data on histologic response determinants to chemotherapy and targeted therapy, with particular attention to the importance of standardized tissue collection, handling, storage, and analysis techniques, in order to best apply the results of tumor analysis to patient-care decisions. Such decisions are related to both improving patient safety and optimizing efficacy with standard chemotherapy as well as newer targeted therapy agents. This entails a change from a generalized approach in treating patients with NSCLC to an individualized strategy based on tumor histology.