COPD is a complex mix of signs and symptoms in patients with chronic bronchitis and emphysema, diseases that largely result from cigarette smoking. Not all smokers, however, acquire COPD, and COPD can develop in nonsmokers. In the United States, COPD is currently the fourth leading cause of death. Surprisingly, there are no effective drug therapies for COPD that are able to significantly alter disease progression, and little is known of the underlying molecular mechanisms that are responsible for its occurrence. Candidate gene-association studies and linkage analyses have been reported for COPD patients. This review describes the genetic predisposition of healthy subjects or relatives of COPD patients to acquire COPD. In addition, the genetic bases of COPD with rapid decline of FEV1 are described, and the current genetic data that have been distilled from studies of COPD patients with a predominant emphysema phenotype, with chronic bronchitis phenotype, and with a response to bronchodilators are discussed.