Lung cancer is the leading cause of cancer deaths worldwide. Recent advance in targeted therapy for lung cancer patients with epidermal growth factor receptor (EGFR) mutations has demonstrated a promising development toward personalized therapy for lung cancer patients. The development of lung cancer is a complex process, involving a series of genetic and epigenetic changes. Tobacco smoke is the predominant etiologic risk factor for lung cancer. However, some lung cancers, especially adenocarcinomas, arise in patients who have never smoked, suggesting the importance of host genetic/epigenetic susceptibility in the occurrence and development of lung cancer. Understanding of these genetic and epigenetic changes will further aid in the biomarker-driven personalized therapy for lung cancer patients. In this review, we summarize the genetic and epigenetic alterations observed in lung cancers, including chromosomal loss of heterozygosity, tumor-suppressor gene mutation, gene methylation, histone modification, and microRNA expression changes. Clinical and preclinical studies have implied specific genetic/epigenetic changes for clinical application in lung cancer patients. However, more efforts are required in validation of the identified molecular markers in lung cancer patients for early detections, assessment for treatment response, and survival predictions.