Lung cancer is the leading cause of cancer-related mortality in the United States. Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Most patients with NSCLC present with locoregionally advanced or metastatic disease, for which response rates and median overall survival remain poor. Platinum-based chemotherapy is the mainstay of treatment for NSCLC in both adjuvant and metastatic disease. Personalized chemotherapy and targeted biologic therapy based on a tumor's histologic and molecular profile have already shown promise in optimizing efficacy. Various markers are currently being investigated for their ability to guide treatment decision-making and management. This article describes these predictive and prognostic markers and details their current role, benefit, and potential future use in the management of patients with NSCLC.